Homology and Relatedness of Amino Acid Interchanges in the Variable Region of κ Light Chains from Human Immunoglobulins

1972 ◽  
Vol 50 (10) ◽  
pp. 1122-1131 ◽  
Author(s):  
M. E. Percy ◽  
J. R. Percy
Keyword(s):  
Amino Acid ◽  
Variable Region ◽  
Light Chains ◽  
Variable Regions ◽  
Amino Terminal ◽  
Functional Homology ◽  
Hypervariable Regions ◽  
Human Immunoglobulins ◽  
Polypeptide Chains ◽  
High Degree

We have devised a method for assessing the relatedness of amino acid interchanges in the variable regions of immunoglobulin polypeptide chains, in terms of the nature of the differences between trinucleotide codons. We have used it to construct a map of the average human κ chain showing the positions which (i) give the chain κ identity, (ii) give the chain subgroup identity within the κ type, (iii) give the chain identity within a subgroup, and (iv) are invariant. In order to determine the positions at which the interchanges are homologous, we have performed a second analysis using the assumption that functionally equivalent amino acids are identical.κ Identity was found throughout the amino-terminal half of the chain (positions 1–108, the variable region). Subgroup identity was not found beyond invariant Phe 98, but was very pronounced in the first 22 positions of the chain. κ and subgroup identity were evident within hypervariable regions (positions 27–35, 48–52, and 90–97), however. A high degree of functional homology was found in the 11 residues at the end of the variable region and at certain individual positions scattered throughout the variable region, but not in the hypervariable regions.The distribution of these different classes of positions might reflect the distribution of certain functions within the chains.

scholarly journals The amino acid sequences of the Fd fragments of two human γ 1 heavy chains

1970 ◽  
Vol 117 (4) ◽  
pp. 641-660 ◽  
Author(s):  
E. M. Press ◽  
N. M. Hogg
Keyword(s):  
Amino Acid ◽  
Aspartic Acid ◽  
Heavy Chain ◽  
Variable Region ◽  
Amino Acid Sequences ◽  
Light Chains ◽  
Aspartic Acid Residue ◽  
Variable Regions ◽  
Heavy Chain Variable Region ◽  
Heavy Chains

The amino acid sequences of the Fd fragments of two human pathological immunoglobulins of the immunoglobulin G1 class are reported. Comparison of the two sequences shows that the heavy-chain variable regions are similar in length to those of the light chains. The existence of heavy chain variable region subgroups is also deduced, from a comparison of these two sequences with those of another γ 1 chain, Eu, a μ chain, Ou, and the partial sequence of a fourth γ 1 chain, Ste. Carbohydrate has been found to be linked to an aspartic acid residue in the variable region of one of the γ 1 chains, Cor.

scholarly journals The specificity of chain interactions among immunoglobulins. Combinations of γ chains with κ chains of the same subgroup as in the parent immunoglobulin G

1974 ◽  
Vol 139 (2) ◽  
pp. 369-374 ◽  
Author(s):  
G. T. Stevenson ◽  
L. E. Mole
Keyword(s):  
Immunoglobulin G ◽  
Structural Information ◽  
Variable Region ◽  
Light Chains ◽  
Predominant Role ◽  
Variable Regions ◽  
Human Immunoglobulins ◽  
Myeloma Proteins ◽  
Standard Population ◽  
Normal Light

1. The specificity of combination of heavy and light chains from selected human immunoglobulins was examined in the light of greater structural information than in previous studies. Heavy (γ) chains from immunoglobulin G (κ) myeloma proteins were allowed to combine with their homologous light (κ) chains or with other κ chains of the same variable-region subgroup. The affinity of each such pairing was assessed by having the test κ chain compete with a standard population of normal light chains. 2. There was a spread of affinities among the heavy–light pairings with the homologous pairings having an average affinity significantly higher than the heterologous pairings. 3. It follows that (a) the preference shown for homologous heavy–light pairings is not explicable simply in terms of the known subdivisions of the variable and constant regions of the chains, and (b) it is unlikely that those residues specifying the subgroups of κ-chain variable regions have a predominant role in the formation of interchain bonds with the γ-chain variable regions.

scholarly journals Complete amino acid sequences of variable regions of two human IgM rheumatoid factors, BOR and KAS of the Wa idiotypic family, reveal restricted use of heavy and light chain variable and joining region gene segments.

1987 ◽  
Vol 166 (2) ◽  
pp. 550-564 ◽  
Author(s):  
M M Newkirk ◽  
R A Mageed ◽  
R Jefferis ◽  
P P Chen ◽  
J D Capra
Keyword(s):  
Amino Acid ◽  
Gene Segment ◽  
Variable Region ◽  
Amino Acid Sequences ◽  
Light Chains ◽  
Rheumatoid Factors ◽  
Region Gene ◽  
Variable Regions ◽  
D Region ◽  
Restricted Use

Evidence derived from the complete amino acid sequences of the variable regions of both the heavy and light chains of two members (BOR and KAS) of the Wa idiotypic family of human rheumatoid factors suggests that not only are the light chains of these molecules derived from possibly one variable region gene segment, but the heavy chain variable regions are all derived from the VHI subgroup of human V region genes. These molecules exhibit a surprising conservation in the size of D region, and all use the JH4 gene element. This restriction in use of VL, VH, D, and JH suggests all of these elements may play a crucial role in either antigen binding and/or expression of the crossreactive idiotype.

scholarly journals Prospective Characterization of Full-Length Hepatitis C Virus NS5A Quasispecies during Induction and Combination Antiviral Therapy

2000 ◽  
Vol 74 (19) ◽  
pp. 9028-9038 ◽  
Author(s):  
J.-B. Nousbaum ◽  
S. J. Polyak ◽  
S. C. Ray ◽  
D. G. Sullivan ◽  
A. M. Larson ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Antiviral Therapy ◽  
Variable Region ◽  
Response To Therapy ◽  
Full Length ◽  
Variable Regions ◽  
C Terminus

ABSTRACT The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein has been controversially implicated in the inherent resistance of HCV to interferon (IFN) antiviral therapy in clinical studies. In this study, the relationship between NS5A mutations and selection pressures before and during antiviral therapy and virologic response to therapy were investigated. Full-length NS5A clones were sequenced from 20 HCV genotype 1-infected patients in a prospective, randomized clinical trial of IFN induction (daily) therapy and IFN plus ribavirin combination therapy. Pretreatment NS5A nucleotide and amino acid phylogenies did not correlate with clinical IFN responses and domains involved in NS5A functions in vitro were all well conserved before and during treatment. A consensus IFN sensitivity-determining region (ISDR237–276) sequence associated with IFN resistance was not found, although the presence of Ala245 within the ISDR was associated with nonresponse to treatment in genotype 1a-infected patients (P < 0.01). There were more mutations in the 26 amino acids downstream of the ISDR required for PKR binding in pretreatment isolates from responders versus nonresponders in both HCV-1a- and HCV-1b-infected patients (P < 0.05). In HCV-1a patients, more amino acid changes were observed in isolates from IFN-sensitive patients (P < 0.001), and the mutations appeared to be concentrated in two variable regions in the C terminus of NS5A, that corresponded to the previously described V3 region and a new variable region, 310 to 330. Selection of pretreatment minor V3 quasispecies was observed within the first 2 to 6 weeks of therapy in responders but not nonresponders, whereas the ISDR and PKR binding domains did not change in either patient response group. These data suggest that host-mediated selective pressures act primarily on the C terminus of NS5A and that NS5A can perturb or evade the IFN-induced antiviral response using sequences outside of the putative ISDR. Mechanistic studies are needed to address the role of the C terminus of NS5A in HCV replication and antiviral resistance.

Chemical structure of light chains: amino acid sequence of type K Bence-Jones proteins

1966 ◽  
Vol 166 (1003) ◽  
pp. 124-137 ◽  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Sequence Data ◽  
Single Point ◽  
Structural Difference ◽  
Light Chains ◽  
Single Point Mutation ◽  
Amino Terminal ◽  
Type K ◽  
Bence Jones Proteins

Bence-Jones proteins are the light chains of the autologous myeloma globulin and are analogous to the light chains of normal human immunoglobulins. Peptide mapping has demonstrated that Bence-Jones proteins share a fixed portion of their sequence (the ‘constant’ portion) and also have a mutable part (the ‘variable’ portion). Sequence analysis and ordering of the tryptic and chymotryptic peptides has provided the tentative complete amino acid sequence of one Bence-Jones protein of antigenic type K. Comparison with partial sequence data for other type K Bence-Jones proteins has revealed many structural differences in the amino terminal half of the molecules, but only one structural difference in the carboxyl terminal half. The latter is strongly correlated with the Inv genetic factor. The points of interchange in the amino terminal half occur in clusters close to the half cystine residues and the ‘switch peptide’ (positions 102 through 105), after which the sequence becomes essentially invariant. This suggests that the major areas subject to sequence variation are part of a single topographical region which may define a portion of the antigen combining site in the light chains of antibodies. Many, but not all, the amino acid interchanges are compatible with a single point mutation. As yet, no single mutational theory suffices to explain the manifold differences in structure of the light chains. Such structural variation, however, could result from the presence of many related genes.

scholarly journals AN ANALYSIS OF THE SEQUENCES OF THE VARIABLE REGIONS OF BENCE JONES PROTEINS AND MYELOMA LIGHT CHAINS AND THEIR IMPLICATIONS FOR ANTIBODY COMPLEMENTARITY

1970 ◽  
Vol 132 (2) ◽  
pp. 211-250 ◽  
Author(s):  
Tai Te Wu ◽  
Elvin A. Kabat
Keyword(s):  
Sequence Data ◽  
Variable Region ◽  
High Variability ◽  
Light Chains ◽  
Variable Regions ◽  
Advantages And Disadvantages ◽  
Specific Subgroup ◽  
Species Specific ◽  
Specific Species ◽  
Bence Jones Proteins

In an attempt to account for antibody specificity and complementarity in terms of structure, human κ-, human λ-, and mouse κ-Bence Jones proteins and light chains are considered as a single population and the variable and constant regions are compared using the sequence data available. Statistical criteria are used in evaluating each position in the sequence as to whether it is essentially invariant or group-specific, subgroup-specific, species-specific, etc. Examination of the invariant residues of the variable and constant regions confirms the existence of a large number of invariant glycines, no invariant valine, lysine, and histidine, and only one invariant leucine and alanine in the variable region, as compared with the absence of invariant glycines and presence of three each of invariant alanine, leucine, and valine and two each of invariant lysine and histidine in the constant region. The unique role of glycine in the variable region is emphasized. Hydrophobicity of the invariant residues of the two regions is also evaluated. A parameter termed variability is defined and plotted against the position for the 107 residues of the variable region. Three stretches of unusually high variability are noted at residues 24–34, 50–56, and 89–97; variations in length have been found in the first and third of these. It is hypothesized that positions 24–34 and 89–97 contain the complementarity-determining residues of the light chain—those which make contact with the antigenic determinant. The heavy chain also has been reported to have a similar region of very high variability which would also participate in forming the antibody-combining site. It is postulated that the information for site complementarity is contained in some extrachromosomal DNA such as an episome and is incorporated by insertion into the DNA of the structural genes for the variable region of short linear sequences of nucleotides. The advantages and disadvantages of this hypothesis are discussed.

scholarly journals The complete amino acid sequence of a prototype immunoglobulin-λ light-chain-type amyloid-fibril protein AR

1981 ◽  
Vol 195 (3) ◽  
pp. 561-572 ◽  
Author(s):  
K Sletten ◽  
J B Natvig ◽  
G Husby ◽  
J Juul
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Light Chain ◽  
Amyloid Fibril ◽  
Variable Region ◽  
Amino Acid Residues ◽  
Variable Regions ◽  
Light Chain Type ◽  
Amyloid Fibril Protein ◽  
Chain Type

The amino acid sequence of an amyloid-fibril protein of immunoglobulin light-chain type (AL) was elucidated. The sequence determination involved digesting the protein with trypsin, thermolysin and pepsin. The protein was found to consist of 154 amino acid residues and is thus missing about half of the constant region of a light chain. A certain heterogeneity in the length of the polypeptide was observed in the C-terminal region. The amino acid sequence from CDR (complementary-determining region) 1 and FR (framework region) 3 indicated an oligoclonal origin of the protein. By comparing the primary structure of protein AR with other lambda- and even kappa-chains, it was revealed that protein AR had an insertion of two residues of aspartic acid, namely residues 68 and 69, which has not been reported previously in light chains. The overall sequence homology in the variable region showed that protein AR is more similar to V lambda V than to the other subgroups [Kabat, Wu & Bilofsky (1979) Variable regions of Immunoglobulin Chains, Medical Computer Systems, Bolt, Beranek and Newman, Cambridge, MA].

scholarly journals PHYLOGENETICALLY ASSOCIATED RESIDUES WITHIN THE VHIII SUBGROUP OF SEVERAL MAMMALIAN SPECIES

1973 ◽  
Vol 138 (2) ◽  
pp. 410-427 ◽  
Author(s):  
J. Donald Capra ◽  
Richard L. Wasserman ◽  
J. Michael Kehoe
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Mammalian Species ◽  
Antibody Diversity ◽  
Heavy Chains ◽  
Amino Terminal ◽  
Myeloma Proteins ◽  
Sequence Homologies ◽  
Protein Sequencer ◽  
High Degree

Immunoglobulin heavy chains from IgG pools of several mammalian species have been subjected to Edman degradation on an automated protein sequencer. The percentage of unblocked vs. blocked heavy chains was estimated from the yield of the invariant valine in the second position. Further analysis of these unblocked polypeptides unequivocally placed them in the VHIII subgroup on the basis of homology with known human heavy chain sequences. The mammals studied could be divided into three distinct categories on the basis of the distribution of the VHIII subgroup. In several species the VHIII subgroup could not be detected while, in others, virtually all of the heavy chains belonged to this subgroup. Several species had intermediate amounts with the level of the VHIII subgroup restricted to between 19 and 29% of the total pool. Within experimental error, all members of a given order had a similar VHIII subgroup distribution. Further amino acid sequence studies illustrated a high degree of structural homogeneity in the heavy chains of IgG isolated from pooled sera of a number of mammalian species. The very close amino acid sequence homologies of the amino terminal 24 residues of the various pools corroborated conclusions previously obtained using several myeloma proteins from some of these same species. In particular, certain phylogenetically associated residues were identifiable at characteristic positions in the pools in confirmation of their identification in the myeloma proteins. The simplest assumptions would suggest that these findings are more compatible with a pauci-gene than a multi-gene basis for the generation of antibody diversity.

Sign in / Sign up

Export Citation Format

Share Document