Three-dimensional structural location and molecular functional effects of missense SNPs in the T cell receptor VP domain

被引:24
作者
Wang, Z
Moult, J
机构
[1] Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA
[2] Univ Maryland, Mol & Cell Biol Grad Program, Rockville, MD 20850 USA
关键词
T-cell receptor; human SNPs; inherited disease; protein structure;
D O I
10.1002/prot.10522
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mechanisms by which human single nucleotide polymorphisms (SNPs) influence susceptibility to disease are not yet well understood. In a previous study, we developed a structure-based model that may be used to identify which missense SNPs are neutral and which are deleterious to protein function and so potentially involved in disease (Wang and Moult, Hum Mutat 2001;263-270). The model has now been applied to a set of 54 missense cSNPs in the 46 functional T-cell receptor Vbeta-genes. Most of these missense cSNPs are found to be neutral, but 10 are identified as likely deleterious to protein function. Only one was previously associated with disease. We suggest that the others may be disease related but that redundancy in the T-cell response prevents any simple, monogenic effect. Therefore, these SNPs are the most likely contributors to complex, polygenic disease traits. It has been noted that there is a surprisingly high (74%) fraction of nonsynonymous SNPs in these genes. Contrary to expectation, the analysis shows that these are not associated with an unusually high fraction of deleterious SNPs, nor do they significantly contribute to a larger range of antigen recognition or a reduced superantigen-binding repertoire. (C) 2003 Wiley-Liss, Inc.
引用
收藏
页码:748 / 757
页数:10
相关论文
共 58 条
[41]   Predicting protein three-dimensional structure [J].
Moult, J .
CURRENT OPINION IN BIOTECHNOLOGY, 1999, 10 (06) :583-588
[42]   Predicting deleterious amino acid substitutions [J].
Ng, PC ;
Henikoff, S .
GENOME RESEARCH, 2001, 11 (05) :863-874
[43]  
Pace CN, 1995, METHOD ENZYMOL, V259, P538
[44]   Structural basis for the recognition of superantigen streptococcal pyrogenic exotoxin A (SpeA1) by MHC class II molecules and T-cell receptors [J].
Papageorgiou, AC ;
Collins, CM ;
Gutman, DM ;
Kline, JB ;
O'Brien, SM ;
Tranter, HS ;
Acharya, KR .
EMBO JOURNAL, 1999, 18 (01) :9-21
[45]   STRUCTURE, EXPRESSION AND DIVERGENCE OF T-CELL RECEPTOR BETA-CHAIN VARIABLE REGIONS [J].
PATTEN, P ;
YOKOTA, T ;
ROTHBARD, J ;
CHIEN, Y ;
ARAI, K ;
DAVIS, MM .
NATURE, 1984, 312 (5989) :40-46
[46]   Genomics and medicine - Dissecting human disease in the postgenomic era [J].
Peltonen, L ;
McKusick, VA .
SCIENCE, 2001, 291 (5507) :1224-+
[47]   Retrograde protein translocation: ERADication of secretory proteins in health and disease [J].
Plemper, RK ;
Wolf, DH .
TRENDS IN BIOCHEMICAL SCIENCES, 1999, 24 (07) :266-270
[48]   Human non-synonymous SNPs: server and survey [J].
Ramensky, V ;
Bork, P ;
Sunyaev, S .
NUCLEIC ACIDS RESEARCH, 2002, 30 (17) :3894-3900
[49]   The crystal structure of a T cell receptor in complex with peptide and MHC class II [J].
Reinherz, EL ;
Tan, KM ;
Tang, L ;
Kern, P ;
Liu, JH ;
Xiong, Y ;
Hussey, RE ;
Smolyar, A ;
Hare, B ;
Zhang, RG ;
Joachimiak, A ;
Chang, HC ;
Wagner, G ;
Wang, JH .
SCIENCE, 1999, 286 (5446) :1913-1921
[50]   The complete 685-kilobase DNA sequence of the human beta T cell receptor locus [J].
Rowen, L ;
Koop, BF ;
Hood, L .
SCIENCE, 1996, 272 (5269) :1755-1762