4UX8

RET recognition of GDNF-GFRalpha1 ligand by a composite binding site promotes membrane-proximal self-association

4UX8 の概要

• エントリーDOI: 10.2210/pdb4ux8/pdb
• EMDBエントリー: 2712
• 分子名称: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET, GDNF FAMILY RECEPTOR ALPHA-1, GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR, ... (5 entities in total)
• 機能のキーワード: signaling protein, vertebrate development, human diseases, part of the ret-gfl- gfra complex
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 269309.39

構造登録者

Goodman, K.,Kjaer, S.,Beuron, F.,Knowles, P.,Nawrotek, A.,Burns, E.,Purkiss, A.,George, R.,Santoro, M.,Morris, E.P.,McDonald, N.Q. (登録日: 2014-08-19, 公開日: 2014-10-01, 最終更新日: 2024-10-23)

主引用文献

Goodman, K.M.,Kjaer, S.,Beuron, F.,Knowles, P.P.,Nawrotek, A.,Burns, E.M.,Purkiss, A.G.,George, R.,Santoro, M.,Morris, E.P.,Mcdonald, N.Q.
Ret Recognition of Gdnf-Gfralpha1 Ligand by a Composite Binding Site Promotes Membrane-Proximal Self-Association.
Cell Rep., 8:1894-, 2014

PubMed Abstract: The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFRα coreceptor, resulting in RET transmembrane signaling. We present a hybrid structural model, derived from electron microscopy (EM) and low-angle X-ray scattering (SAXS) data, of the RET extracellular domain (RET(ECD)), GDNF, and GFRα1 ternary complex, defining the basis for ligand recognition. RET(ECD) envelopes the dimeric ligand complex through a composite binding site comprising four discrete contact sites. The GFRα1-mediated contacts are crucial, particularly close to the invariant RET calcium-binding site, whereas few direct contacts are made by GDNF, explaining how distinct ligand/coreceptor pairs are accommodated. The RET(ECD) cysteine-rich domain (CRD) contacts both ligand components and makes homotypic membrane-proximal interactions occluding three different antibody epitopes. Coupling of these CRD-mediated interactions suggests models for ligand-induced RET activation and ligand-independent oncogenic deregulation.

PubMed: 25242331
DOI: 10.1016/J.CELREP.2014.08.040

実験手法

ELECTRON MICROSCOPY (24 Å)