Evolution of GITRL immune function: Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily

被引：61

作者：

Chattopadhyay, Kausik ^{[1
]}

Ramagopall, Udupi A. ^{[3
]}

Brenowitz, Michael ^{[3
]}

Nathenson, Stanley G. ^{[1
,2
]}

Almo, Steven C. ^{[3
,4
]}

机构：

[1] Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA

[2] Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA

[3] Yeshiva Univ Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA

[4] Yeshiva Univ Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 02期

关键词：

crystal structure; domain swap; oligomerization; T cell costimulation;

D O I：

10.1073/pnas.0710529105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. In contrast to all previously characterized homotrimeric TNF family members, the mouse GITRL crystal structure reveals a previously unrecognized dimeric assembly that is stabilized via a unique "domain-swapping" interaction. Consistent with its crystal structure, mouse GITRL exists as a stable dimer in solution. Structure-guided mutagenesis studies confirmed the determinants responsible for dimerization and support a previously unrecognized receptor-recognition surface for mouse GITRL that has not been observed for any other TNF family members. Taken together, the unique structural and biochemical behavior of mouse GITRL, along with the unusual domain organization of murine GITR, support a previously unrecognized mechanism for signaling within the TNF superfamily.

引用

页码：635 / 640

页数：6

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