Structural determinants in the sequences of immunoglobulin variable domain 1 1Edited by A. R. Fersht

Chothia, Cyrus; Gelfand, Israel M.; Kister, Alexander

doi:10.1006/jmbi.1998.1653

Cited by 170 publications

(159 citation statements)

References 64 publications

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“…Additionally, Thr in place of the conserved Ala at position 84 in a human -chain proved to be destabilizing (20). Phe 62 also contributes to the stabilization of this hydrophobic core (18), and others have shown replacing a polar Ser for the conserved Phe impairs L chain secretion (see Fig. 4C) (12).…”

Section: Structural Consequences Of Secretion-restoring Mutationsmentioning

confidence: 93%

Restoration of Ig Secretion: Mutation of Germline-Encoded Residues in T15L Chains Leads to Secretion of Free Light Chains and Assembled Antibody Complexes Bearing Secretion-Impaired Heavy Chains

Whitcomb

Martin

Rittenberg

2003

The Journal of Immunology

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We previously described T15H chain mutants that were impaired in assembly with L chain and in ability to be secreted from the cell. The unmutated T15L chain is unusual in that it is secretion-impaired in the absence of assembly with H chain. The T15L chain preferentially pairs with T15H in vivo, suggesting that if we introduced mutations that would allow secretion of free T15L chain, they might also lead to the secretion of the complex with the defective H chain. We mutated four positions in the germline T15L that had amino acids infrequently found in other κ-chains. Mutation to the most frequently occurring amino acid at three of the four positions allowed secretion of free L chain, while the combination of two secretion-restoring mutations was synergistic. Coexpression of secretion-restored mutant L chains with the secretion-defective mutant H chains rescued secretion of the assembled H2L2 complex, suggesting that during somatic hypermutation in vivo, deleterious mutations at the H chain may be compensated by mutations on the L chain. To our knowledge, this is the first example of mutations in IgL chains that are able to restore secretion-defective H chains to secretion competence in mammalian cells.

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Section: Structural Consequences Of Secretion-restoring Mutationsmentioning

confidence: 93%

Restoration of Ig Secretion: Mutation of Germline-Encoded Residues in T15L Chains Leads to Secretion of Free Light Chains and Assembled Antibody Complexes Bearing Secretion-Impaired Heavy Chains

Whitcomb

Martin

Rittenberg

2003

The Journal of Immunology

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“…The dossier includes (i) residue characteristic (21,23); (ii) values of accessibility of residues to the solvent (23); (iii) data of the residue-residue contacts (23); (iv) the average coordinates of C␣ atoms in the invariant system of coordinates of Ig molecules (7) and other structural and functional properties (21). The role of residues at each position of a word was determined from the examination of Ͼ5,300 sequences in the Kabat database (1) and Ͼ100 threedimensional Ig structures from a protein database (7-8, 21, 23).…”

Section: Stage II Classification Of Positions Of Residues In Wordsmentioning

confidence: 99%

“…It is important to note that either of the two sets of positions can be used to arrive to the same six-class classification of the human heavy chains. A significant corollary of our approach is that once a class of a sequence is known, its secondary structure, values of surface accessibility of residues, most favorable residueresidue contacts in a structure, and coordinates of main chain atoms in the invariant system of coordinate for Ig family also are known (23).…”

Section: Stage IV Classification and Patterns Of Sequencesmentioning

confidence: 99%

“…Our approach to this problem follows along the lines of our previous investigations of the Ig family (7)(8)(21)(22)(23). Process of classification of sequences of the variable domains is divided into four stages:…”

mentioning

confidence: 99%

“…Much sequence and structural data were analyzed to define words and positions of residues in words. It was shown that residues occupying identical positions in different molecules revealed a large number of similarities; they had approximately same coordinates of C␣ atoms in the invariant system of coordinates of the variable domains (7,8), similar residueresidue contacts (23), similar H-bonds between main chain atoms (21), approximately same values of accessibility to a solvent (21,23), and other common properties.…”

mentioning

confidence: 99%

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Predicting amino acid sequences of the antibody human V _H chains from its first several residues

Galitsky¹,

Gelfand²,

Kister³

1998

Proc. Natl. Acad. Sci. U.S.A.

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A new method for classification of Ig sequences is suggested. The defining characteristic of a class is presence of particular residues at several class-determining positions. Sequences within a class follow the same amino acid pattern, i.e., residues at identical positions are, in an overwhelming majority of sequences of that class, identical or chemically related. Thus, once the class of a sequence is determined, one can predict the residue(s) at almost any position in the sequence. In this paper, results of analysis of 1,172 human heavy chains are presented. It was shown that a sequence can be assigned to one of six classes depending on which residues are found at its positions 1, 3, 5, 6, 7, 9, 10, 12, and 13. It is important to note that it is possible to achieve same six-class classification of the human heavy chains on the basis of a different set of positions found not at the beginning but near the end of the sequence (around position 80). For every class, an amino acid pattern of an entire sequence (complementarity determining regions excepting) has been determined. Our approach allowed us to reconstruct the incomplete human heavy chains in which residues at certain positions at the beginning or end of the chain are known. We developed a software tool for analysis, classification, and prediction of residues in sequences of the Ig family.

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Covariance analysis of protein families: The case of the variable domains of antibodies

Choulier¹,

Lafont²,

Hugo³

et al. 2000

Proteins

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A nonrestrictive method for identifying covariance in protein families is described and applied to human and mouse germline Vκ and VH sequence alignments. Amino acids that occur at each position in a sequence alignment are divided into two sets, called a word, by generating all possible combinations of alternative amino acids. Each word is associated with a pattern of changes. Words with identical patterns identify covariant positions. In antibody variable domains, the number of words generated ranged between 1103 and 2195 depending on the alignment, of which 4 to 12 % occurred in covariant pairs. Despite the nonrestrictive character of pattern generation, covariant residues did not reflect a random selection with respect to the nature of amino acid changes and/or their spatial proximity in a reference crystallographic structure. This approach allowed the identification of a covariance signal for positions with high variability, mostly located in the outer part of the common structural framework of antibody variable domains. Covariance in these regions may reflect the existence of alternative and mutually exclusive atomic arrangements that are compatible with antibody function. The method may be of general applicability to rationalize residue variability in protein families. Proteins 2000;41:475–484. © 2000 Wiley‐Liss, Inc.

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Structural determinants in the sequences of immunoglobulin variable domain 1 1Edited by A. R. Fersht

Cited by 170 publications

References 64 publications

Restoration of Ig Secretion: Mutation of Germline-Encoded Residues in T15L Chains Leads to Secretion of Free Light Chains and Assembled Antibody Complexes Bearing Secretion-Impaired Heavy Chains

Restoration of Ig Secretion: Mutation of Germline-Encoded Residues in T15L Chains Leads to Secretion of Free Light Chains and Assembled Antibody Complexes Bearing Secretion-Impaired Heavy Chains

Predicting amino acid sequences of the antibody human V _H chains from its first several residues

Covariance analysis of protein families: The case of the variable domains of antibodies

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Structural determinants in the sequences of immunoglobulin variable domain 1 1Edited by A. R. Fersht

Cited by 170 publications

References 64 publications

Restoration of Ig Secretion: Mutation of Germline-Encoded Residues in T15L Chains Leads to Secretion of Free Light Chains and Assembled Antibody Complexes Bearing Secretion-Impaired Heavy Chains

Restoration of Ig Secretion: Mutation of Germline-Encoded Residues in T15L Chains Leads to Secretion of Free Light Chains and Assembled Antibody Complexes Bearing Secretion-Impaired Heavy Chains

Predicting amino acid sequences of the antibody human V H chains from its first several residues

Covariance analysis of protein families: The case of the variable domains of antibodies

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Product

Resources

About

Predicting amino acid sequences of the antibody human V _H chains from its first several residues