With varying clinical symptoms, most neurodegenerative diseases are associated with abnormal loss of neurons. They share the same common pathogenic mechanisms involving misfolding and aggregation, and these visible aggregates of proteins are deposited in the central nervous system. Amyloid formation is thought to arise from partial unfolding of misfolded proteins leading to the exposure of hydrophobic surfaces, which interact with other similar structures and give rise to form dimers, oligomers, protofibrils, and eventually mature fibril aggregates. Accumulating evidence indicates that amyloid oligomers, not amyloid fibrils, are the most toxic species that causes Alzheimer's disease (AD) and Parkinson's disease (PD). AD has recently been recognized as the 'twenty-first century plague', with an incident rate of 1% at 60 years of age, which then doubles every fifth year. Currently, 5.3 million people in the US are afflicted with this disease, and the number of cases is expected to rise to 13.5 million by 2050. PD, a disorder of the brain, is the second most common form of dementia, characterized by difficulty in walking and movement. Keeping the above views in mind, in this review we have focused on the roles of amyloid in neurodegenerative diseases including AD and PD, the involvement of amyloid in mitochondrial dysfunction leading to neurodegeneration, are also considered in the review.

Protein misfolding and aggregation can be induced by a wide variety of factors, such as dominant disease-associated mutations, changes in the environmental conditions (pH, temperature, ionic strength, protein concentration, exposure to transition metal ions, exposure to toxins, posttranslational modifications including glycation, phosphorylation, and sulfation). Misfolded intermediates interact with similar intermediates and progressively form dimers, oligomers, protofibrils, and fibrils. In amyloidoses, fibrillar aggregates are deposited in the tissues either as intracellular inclusion or extracellular plaques (amyloid). When such proteinaceous deposit occurs in the neuronal cells, it initiates degeneration of neurons and consequently resulting in the manifestation of various neurodegenerative diseases. Several different types of molecules have been designed and tested both in vitro and in vivo to evaluate their anti-amyloidogenic efficacies. For instance, the native structure of a protein associated with amyloidosis could be stabilized by ligands, antibodies could be used to remove plaques, oligomer-specific antibody A11 could be used to remove oligomers, or prefibrillar aggregates could be removed by affibodies. Keeping the above views in mind, in this review we have discussed protein misfolding and aggregation, mechanisms of protein aggregation, factors responsible for aggregations, and strategies for aggregation inhibition.

With varying clinical symptoms, most neurodegenerative diseases are associated with abnormal loss of neurons. They share the same common pathogenic mechanisms involving misfolding and aggregation, and these visible aggregates of proteins are deposited in the central nervous system. Amyloid formation is thought to arise from partial unfolding of misfolded proteins leading to the exposure of hydrophobic surfaces, which interact with other similar structures and give rise to form dimers, oligomers, protofibrils, and eventually mature fibril aggregates. Accumulating evidence indicates that amyloid oligomers, not amyloid fibrils, are the most toxic species that causes Alzheimer's disease (AD) and Parkinson's disease (PD). AD has recently been recognized as the 'twenty-first century plague', with an incident rate of 1% at 60 years of age, which then doubles every fifth year. Currently, 5.3 million people in the US are afflicted with this disease, and the number of cases is expected to rise to 13.5 million by 2050. PD, a disorder of the brain, is the second most common form of dementia, characterized by difficulty in walking and movement. Keeping the above views in mind, in this review we have focused on the roles of amyloid in neurodegenerative diseases including AD and PD, the involvement of amyloid in mitochondrial dysfunction leading to neurodegeneration, are also considered in the review.

Alzheimer's disease (AD) is the most common form of age-related neurodegeneration occurs because of deposition of proteins in the form of extracellular plaques containing aggregated amyloid beta (A beta) peptide and intracellular neurofibrillary tangles composed of aggregated microtubule-binding protein tau. Amyloid aggregation process can be enhanced by several familial AD-associated mutations in A beta peptide. In this study, we have unravelled the interactions of 40 small molecule inhibitors with the Osaka-mutant of A beta(1-40) peptide at atomic level and characterized modes of their binding to mutant A beta by docking approaches. We have also compared docking energies of these inhibitors with Osaka-mutant with those previously determined for the wild-type and Iowa-mutant peptides and discussed in light of the peptide conformations and non-covalent interactions. We have also discussed inhibition mechanisms of these three peptides. Our analyses revealed that these small molecules can efficiently inhibit Osaka-mutant. The binding modes of drugs with these three peptides are markedly different and so are the mechanisms of inhibition of these three peptides. Overall analysis of the data reveals that binding energy of Iowa-mutant drug complex is lowest and most stable which is followed wild-type peptide-drug complex followed by Osaka-mutant drug complex. Communicated by Ramaswamy H. Sarma

Alzheimer's disease (AD) is the most common form of neurodegenerative diseases, characterized by the deposition of Aβ (amyloid beta) peptide. In this study, we have unravelled the interactions as well as anti amyloidogenic behaviour of 40 small molecule inhibitors with Aβ1-40 peptide and Iowa mutant D23N-Aβ115-42 peptide at atomic level and their modes of binding by docking approaches. The binding mode between wild type peptide and drug is distinctly different from the Iowa-mutant-peptide and drug. Here we proposed possible mechanisms of amyloid beta peptide inhibition by small molecule and prevent monomer-monomer interactions via at least three different mechanisms. In the first mechanism, four catechins efficiently interacted with the C-terminal region of peptides through hydrogen bonds and inhibited the peptides. This may lead to blockage of access of second molecule of Aβ-peptide. Secondly, in the case Iowa mutant D23N-Aβ15-42 peptide, same catechin form hydrogen bond with the important mutated Asn23 residue which acts as hydrogen bond donor and acceptor leading to tight binding of inhibitor with the peptide and may prevent monomer-monomer interactions. The third mechanism relies on the ability of drug molecules to mask hydrophobic residues of the peptide, thereby possibly inhibiting hydrophobic interactions between the two beta peptides.

Alzheimer's disease (AD) is one of the most common age-related diseases that occurs because of the deposition of amyloid fibrils in a form of extracellular plaques containing β-amyloid peptide (Aβ) and tangles are found as intracellular deposit in the brain made up of twisted strands of aggregated microtubule binding protein. Scores of small molecule inhibitors have been designed for the treatment of AD. However some of these drugs cannot pass through the brain-blood-barrier (BBB). To overcome this problem, various nanoparticles (NPs) or nanomedicines (NMs) have been synthesized. These nanoparticles exploit the existing physiological mechanisms of passing through the BBB, including receptor- and adsorptive-mediated transcytosis that facilitate the transcellular transport of nanoparticle from the blood to the brain. During the last decades, varieties of nanoparticles that differ in the composition have been developed, and they have the potential application in the diagnostics and therapy of AD. The most common NP formulations that have major impact in the diagnosis and therapy of AD include polymeric NPs (PPs), gold NPs, gadolinium NPs, selenium NPs, protein-based NPs, polysaccharide-based NPs, etc. The goal of this review is to provide discussion of the application of different types of NP formulations in the diagnosis and therapy of AD.

Antibiotic resistance in gram-negative bacteria has emerged as a major health threat that occurs because these bacteria actively produce β-lactamases responsible for the inactivation of β-lactam antibiotics. The first β lactamase was reported in E. coli back in 1940, before the release of the first antibiotic penicillin in clinical settings. Later on, large numbers of β-lactamases have been discovered in Gram-positive, Gram-negative bacteria as well as mycobacteria. Currently, numerous three-dimensional structures of serine and metallo-β-lactamases have been solved. The serine β-lactamases essentially consist of two structural domains (an all α and an α/β domain) and the active site is located at the groove between the two domains. The catalysis of serine β-lactamase proceeds via acylation and deacylation reactions. The three dimensional structure of metallo-β-lactamases displayed a common four layer "αβ/βα" motif, with a central "ββ"- sandwich by Zn2+ ion(s), and two α-helices are located on the either side. The active site of metallo-β-lactamases contain either 1 or 2 Zn2+ ions, which is coordinated to metal ligating amino acids and polarized water molecule(s) necessary for the hydrolysis of β-lactam antibiotics. Keeping the above views in mind, in this review we have shed light on the current knowledge of the structures and mechanisms of catalysis of serine and metallo-β-lactamases. Moreover, mutational studies on β-lactamases highlight the importance of the active site residues and residues in the vicinity to the active site pocket in the catalysis. To combat bacterial infections more effeciently novel inhibitors of β-lactamase in combination with antibiotics have been used which also form the theme of the review.

Protein homeostasis (proteostasis) is achieved by the interplay among various components and pathways inside a cell. Dysfunction in proteostasis leads to protein misfolding and aggregation which is ubiquitously associated with many neurodegenerative disorders, although the exact role of these aggregate in the pathogenesis remains unknown. Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and others are characterized by the conversion of specific protein aggregates into protein inclusions and/or plaques in degenerating brains. Apart from the conventional disease specific proteins, such as amyloid-beta, alpha-synuclein, huntingtin protein, and prions that are known to aggregate, a number of other proteins play a vital role in aggravating the disease condition. In this review, we discuss the disease etiology, mechanism, the role of various pathways, molecular machinery including molecular chaperones, protein degradation pathways, and the active formation of inclusions in various neurodegenerative diseases. We also highlight the approaches, strategies, and methods that have been used for the treatment of these complex diseases over the years and the efforts that have potential in the near future.

Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily of redox proteins. Originally, PDI was identified in the lumen of the endoplasmic reticulum and subsequently detected abundantly in many other tissues and account for 0.8% of total cellular protein. PDI consists of four tandem thioredoxin-like domains a, b, b′, and a′ plus a C-terminal extension which are arranged into a U-shape structure. PDI has three catalytic activities including, thiol-disulfide oxidoreductase, disulfide isomerase and redox-dependent chaperone. Now the functions ascribed to PDI have evolved significantly because recent studies have shown that it has detrimental as well as protective effects in diseases states. Keeping the above views in mind, in this review we have discussed the structure of PDI, its catalytic and chaperone activity and its role in various diseases states.

In protein misfolding, protein molecule acquires wrong tertiary structure, thereby induces protein misfolding diseases. Protein misfolding can occur through various mechanisms. For instance, changes in environmental conditions, oxidative stress, dominant negative mutations, error in post-translational modifications, increase in degradation rate and trafficking error. All of these factors cause protein misfolding thereby leading to diseases conditions. Both in vitro and in vivo observations suggest that partially unfolded or misfolded intermediates are particularly prone to aggregation. These partially misfolded intermediates aggregate via the interaction with the complementary intermediates and consequently enhance oligomers formation that grows into fibrils and proto-fibrils. The amyloid fibrils for example, accumulate in the brain and central nervous system (CNS) as amyloid deposits in the Parkinson's disease (PD), Alzheimer's disease (AD), Prion disease and Amylo lateral Sclerosis (ALS). Furthermore, tau protein shows intrinsically disorder conformation; therefore its interaction with microtubule is impaired and this protein undergoes aggregation. This is also underlying cause of Alzheimers and other neurodegenerative diseases. Treatment of such misfolding maladies is considered as one of the most important challenges of the 21st century. Currently, several treatments strategies have been and are being discovered. These therapeutic interventions partly reversed or prevented the pathological state. More recently, a new approach was discovered, which employs nanobodies that targets multisteps in fibril formation pathway that may possibly completely cure these misfolding diseases. Keeping the above views in mind in the current review, we have comprehensively discussed the different mechanisms underlying protein misfolding thereby leading to diseases conditions and their therapeutic interventions. (C) 2016 Elsevier B.V. All rights reserved.

Protein misfolding is one of the leading causes of amyloidoses. Protein misfolding occurs from changes in environmental conditions and host of other factors, including errors in post-translational modifications, increase in the rate of degradation, error in trafficking, loss of binding partners and oxidative damage. Misfolding gives rise to the formation of partially unfolded or misfolded intermediates, which have exposed hydrophobic residues and interact with complementary intermediates to form oligomers and consequently protofibrils and fibrils. The amyloid fibrils accumulate as amyloid deposits in the brain and central nervous system in Alzheimer's disease (AD), Prion disease and Parkinson's disease (PD). Initial studies have shown that amyloid fibrils were the main culprit behind toxicity that cause neurodegenerative diseases. However, attention shifted to the cytotoxicity of amyloid fibril precursors, notably amyloid oligomers, which are the major cause of toxicity. The mechanism of toxicity triggered by amyloid oligomers remains elusive. In this review, we have focused on the current knowledge of the structures of different aggregated states, including amyloid fibril, protofibrils, annular aggregates and oligomers. Based on the studies on the mechanism of toxicities, we hypothesize two major possible mechanisms of toxicities instigated by oligomers of Aβ (amyloid beta), PrP (prion protein) (106–126), and α-Syn (alpha-synuclein) including direct formation of ion channels and neuron membrane disruption by the increase in membrane conductance or leakage in the presence of small globulomers to large prefibrillar assemblies. Finally, we have discussed various novel innovative approaches that target amyloid oligomers in Alzheimer's diseases, Prion disease and Parkinson's disease.

In vitro refolding studies are considered as a good model to understand the mechanism by which polypeptide chain acquires unique three dimensional structure in the cell. However, the intracellular environment is highly crowded containing about 300-400 mg/ml of macromolecules. These conditions would promote improper associations among protein molecules leading to aggregation. But protein folds beautifully in the complex cellular environment. This eventually led to the discovery of molecular chaperone that revolutionized the concept of protein folding in the cell. Molecular chaperone is defined as any protein that interacts, stabilizes or helps a non-native protein to acquire the native structure but is not a part of the final structure. Chaperones that participate in protein biogenesis primarily recognize exposed hydrophobic surface of protein and promote their folding through ATP-regulated cycles of binding and release. Failure of the chaperone network to maintain proteostasis, i.e. the conformational integrity of the cellular proteome, may results in the manifestation of pathological states including Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Amylolateral Sclerosis disease, in which proteins misfold and are deposited as aggregates [2] . In view of above, in this review, I have discussed current status of protein folding in the cell with special reference to chaperone pathways in de novo folding, chaperones acting downstream of the ribosome, proteostasis network and proteostasis network as drug target.

Protein folding is one of the most perplexing problems in molecular biology. Protein folding is a complex process through which protein molecule acquires unique native structure which carry out specific biological function. However, recently it has been recognized that some proteins have no single well-defined tertiary structure.These proteins are termed intrinsically disordered protein (IDP) which are involved in regulation and signaling. In 1969, Cyrus Levinthal noted that, because of the very large number of degrees of freedom in an unfolded polypeptide chain, the protein molecule has an astronomical number of possible conformations. Hence, from one calculation, for 100 amino acids polypeptide chain, 1011 years will be required for protein to fold, which is an unrealistic time because in vivo protein folding occurs in seconds or minutes. This is known as Levinthal paradox. To overcome Levinthal paradox, several folding models have been proposed. This includes from classical nucleation-propagation model to folding funnel model. The in vitro and in vivo conditions of protein folding are not the same.This was particularly challenged by the discovery of molecular chaperones that assist in correct folding of protein and if protein still misfolds it is subjected to proteasomal degradation for the maintenance of cell homeostasis. Despite of cellular protein quality control proteins often misfold. This happens due to mutations, changes in environmental conditions and includes many more factors. These misfolded proteins give rise to increase population of partially misfolded intermediates which have exposed hydrophobic residues that interact with complementary intermediates and consequently results in the formation of oligomers thereby proto-fibrils and fibrils. These fibrils are deposited in the brain and CNS leading to the manifestation of neurodegenerative diseases. Keeping above views in mind, in this review I have focused on, various folding models, folding in the cell, misfolding, aggregation and mechanism of Aβ fibril formation. Since Aβ oligomers are now considered as more toxic entities than fibrils. Hence, their mechanisms of toxicities also form the theme of the review.

The β-lactamases enzymes cleave the amide bond in β-lactam ring, rendering β-lactam antibiotics harmless to bacteria. In this communication we have studied structure-function relationship and phylogenies of class A, B and D beta-lactamases using structure-based sequence alignment and phylip programs respectively. The data of structure-based sequence alignment suggests that in different isolates of TEM-1, mutations did not occur at or near sequence motifs. Since deletions are reported to be lethal to structure and function of enzyme. Therefore, in these variants antibiotic hydrolysis profile and specificity will be affected. The alignment data of class A enzyme SHV-1, CTX-M-15, class D enzyme, OXA-10, and class B enzyme VIM-2 and SIM-1 show sequence motifs along with other part of polypeptide are essentially conserved. These results imply that conformations of betalactamases are close to native state and possess normal hydrolytic activities towards beta-lactam antibiotics. However, class B enzyme such as IMP-1 and NDM-1 are less conserved than other class A and D studied here because mutation and deletions occurred at critically important region such as active site. Therefore, the structure of these beta-lactamases will be altered and antibiotic hydrolysis profile will be affected. Phylogenetic studies suggest that class A and D beta-lactamases including TOHO-1 and OXA-10 respectively evolved by horizontal gene transfer (HGT) whereas other member of class A such as TEM-1 evolved by gene duplication mechanism. Taken together, these studies justify structure-function relationship of beta-lactamases and phylogenetic studies suggest these enzymes evolved by different mechanisms.

Protein glycation is initiated by a nucleophilic addition reaction between the free amino group from a protein, lipid or nucleic acid and the carbonyl group of a reducing sugar. This reaction forms a reversible Schiff base, which rearranges over a period of days to produce ketoamine or Amadori products. The Amadori products undergo dehydration and rearrangements and develop a cross-link between adjacent proteins, giving rise to protein aggregation or advanced glycation end products (AGEs). A number of studies have shown that glycation induces the formation of the β-sheet structure in β-amyloid protein, α-synuclein, transthyretin (TTR), copper-zinc superoxide dismutase 1 (Cu, Zn-SOD-1), and prion protein. Aggregation of the β-sheet structure in each case creates fibrillar structures, respectively causing Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, and prion disease. It has been suggested that oligomeric species of glycated α-synuclein and prion are more toxic than fibrils. This review focuses on the pathway of AGE formation, the synthesis of different types of AGE, and the molecular mechanisms by which glycation causes various types of neurodegenerative disease. It discusses several new therapeutic approaches that have been applied to treat these devastating disorders, including the use of various synthetic and naturally occurring inhibitors. Modulation of the AGE-RAGE axis is now considered promising in the prevention of neurodegenerative diseases. Additionally, the review covers several defense enzymes and proteins in the human body that are important anti-glycating systems acting to prevent the development of neurodegenerative diseases.

Influenza A virus subtype H5N1, also known as "bird flu" has been documented to cause an outbreak of respiratory diseases in humans.The unprecedented spread of highly pathogenic avian influenza type A is a threat to veterinary and human health.The BFluenza is a relational database which is solely devoted to proteomic information of H5N1 subtype.Bfluenza has novel features including computed physico-chemical properties data of H5N1 viral proteins, modeled structures of viral proteins, data of protein coordinates, experimental details, molecular description and bibliographic reference.The database also contains nucleotide and their decoded protein sequences data.The database can be searched in various modes by setting search options.The structure of viral protein could be visualized by JMol viewer or by Discovery Studio.

Alpha-1-antitrypsin (AAT) deficiency was first described in 1963 by Laurell and Eriksson (Laurell & Eriksson, 1963). They reported an absence of the alpha-1-band in electrophoresis. Alpha -1 -antitrypsin deficiency is one of the most common lethal hereditary disorder of Caucasians of European descent. Alpha -1antitrypsin also known as α-1-proteinase inhibitor is an archetypal member of the serine proteinase inhibitors, ”serpins”. The function of alpha -1antitrypsin is to protect the lower respiratory tract of lungs from proteolytic attack by neutrophil elastase (NE) (Carrell et al., 1982; Brantly et al., 1988). The low circulating levels of AAT expose the lungs to uncontrolled proteolytic attack and predispose the Z homozygous to early-onset panlobular emphysema (Brantly et al., 1988) and liver diseases (Sharp et al., 1969; Sveger, 1976; Eriksson et al., 1986). AAT is synthesized primarily by hepatocytes (Koj et al., 1978; Eriksson et al., 1978) and also by other cells such as monocytes, macrophages, breast carcinoma cells and cornea (Boskovic & Twing, 1998; Geboes et al., 1982; Perlmutter et al., 1985; Ray et al., 1977). In addition, there is a local production of AAT within the lungs by alveolar macrophages and epithelial cells. AAT is present in the plasma at concentrations of 190-280 mg/dl. AAT is a single chain glycoprotein of molecular weight 52kDa containing 394 amino acid residues with the active site residue methionine located at amino acid position 358. AAT also contains three oligosaccharide chains linked to Asn 46, Asn83 and Asn247 respectively. AAT is encoded at the PI locus on chromosome 14 (14q24.3-q32.1) (Cox, 1982, 1985; Schroeder et al., 1985). The PI locus is 12.2 kb in length with 4 coding exons (II, III, IV, and V), 3 noncoding exons (IA, IB, IC) and 6 introns; the region coding for the reactive site loop is located in exon V. AAT shows co-dominant pattern of inheritance (Eriksson, 1965). Accumulating evidence shows that AAT may also exhibit anti-inflammatory activities independent of its protease inhibitor function (Dabbagh et al., 2001; Jeannin et al., 1998; Ikari et al., 2001; Weiss et al., 1993; Bucurenci et al., 1992). For example AAT has been shown to stimulate fibroblast proliferation and procollagen synthesis (Dabbagh et al., 2001) and up-regulate human B cell differentiation into IgE-and IgG4-secreting cells (Jeannin et al., 1998). AAT also inhibits neutrophil superoxide production (Bucurenci et al., 1992), induces the release of macrophage derived interleukin-1 receptor antagonist (Churg et al., 2001) and reduces bacterial endotoxin and TNFα lethal effect in vivo (Jie et al., 2003; Libert et al., 1996). AAT also increases the expression of cytokine IL-10 (Janciauskiene et al., 2007). A novel finding indicates that AAT protects the insulin secreting β-cells of pancreas from apoptosis (Zhang et al.,2007).

Influenza A virus (H1N1), a genetic reassortment of endemic strains of human, avian and swine flu, has crossed species barrier to human and apparently acquired the capability of human to human transmission. Some strains of H5N1 subtype are highly virulent because NS1 protein inhibits antiviral interferon α/β production. Another protein NS2 mediates export of viral ribonucleoprotein from nucleus to the cytoplasm through export signal. In this paper, we have studied structure-function relationships of these proteins of H1N1 subtype and have determined the cause of their pathogenicity. Our results showed that non-conservative mutations slightly stabilized or destabilized structural domains of NS1 or NS1-dsRNA complex, hence slightly increased or decreased the function of NS1 protein and consequently enhanced or reduced the pathogenicity of the H1N1 virus. NS2 protein of different strains carried non-conservative mutations in different domains, resulting in slight loss of function. These mutations slightly decreased the pathogenicity of the virus. Thus, the results confirm the structure-function relationships of these viral proteins.

antitrypsin ( 1-AT) is a 52 kDa sialoglycoprotein. The function of  1-antitrypsin is to protect the lower res- piratory tract of lungs from proteolytic degradation by neutrophil elastase. Severe genetic deficiency of  1-AT is associ- ated with early onset emphysema and liver diseases.  1-AT also exhibits anti-inflammatory activities independent of its protease inhibitor function. There are over 90 genetic variants of human  1-antitrypsin. These variants occur due to amino acid substitution / deletion which results in charge differences. Based on charge differences these variants have been iden- tified by isoelectric focusing. The two most common deficiency variants are S and Z. The S variant migrates anodal to Z variant. The Z variant migrates most cathodal in isoelectric focusing, hence named Z. In Z variant, the  -sheet A under- goes expansion , therefore it can easily accepts the reactive site loop of a second  1-AT molecule and consequently form polymers of  1-AT. These polymers of  1-AT aggregate in the hepatocytes and show liver and lungs diseases. Contrary to this, the S variant of  1-AT is not associated with any significant clinical disease because the conformation of the inhibitor is not altered significantly. The Z related pathologies could be treated by liver transplantation, augmentation therapy, gene therapy, peptide therapy and chemical chaperone therapy. In addition to common deficiency variants, there are several rare deficiency variants of  1-AT like Siiyama , Mmalton , Mprocida, Mheerlen, Mmineral springs, Mnichinan, Pduarte, Wbethesda Zaugsberg, and Zbristol. In Siiyama , Mmalton , Mnichinan and Zaugsberg, the  -sheet A is present in an open state therefore these variants readily undergo polymerization and consequently show aggregation in the hepatocytes. In Mprocida, Mheerlen, Mmineral springs, Pduarte and Wbethesda the conformation is altered significantly therefore these variants become conformationally less stable and thereby undergo intracellular proteolysis. These rare genetic vari- ants show lungs and / or liver disease. There are several null variants of  1-AT that are not detected either at the stage of transcription or translation. The examples of some of the null variants are QOcardiff, QOhong kong, QOgranite falls, QObellingham, QOmattawa, QObolton, and QOludwigshafen. The molecular basis of deficiency of these variants also form the theme of this review.