PDBsum entry 2x2u

Transferase

PDB id: 2x2u

Contents

Protein chain

236 a.a.

Ligands

NAG-NAG

UNX-UNX ×2

UNX ×4

UNX-UNX-UNX

SO4 ×8

BU1 ×2

Waters ×216

References listed in PDB file

Key reference

• Title: Mammal-Restricted elements predispose human ret to folding impairment by hscr mutations.
• Authors: S.Kjaer, S.Hanrahan, N.Totty, N.Q.Mcdonald.
• Ref.: Nat Struct Biol, 2010, 17, 726-731.
• PubMed id: 20473317

Abstract

The maturation of human RET is adversely affected by a range of missense mutations found in patients with Hirschsprung's disease (HSCR), a complex multigenic disease. Here we show that two N-terminal cadherin-like domains, CLD1 and CLD2 (CLD(1-2)), from human RET adopt a clam-shell arrangement distinct from that of classical cadherins. CLD1 structural elements and disulfide composition are unique to mammals, indicating an unexpected structural diversity within higher and lower vertebrate RET CLD regions. We identify two unpaired cysteines that predispose human RET to maturation impediments in the endoplasmic reticulum and establish a quantitative cell-based RET maturation assay that offers a biochemical correlate of HSCR disease severity. Our findings provide a key conceptual framework and means of testing and predicting genotype-phenotype correlations in HSCR.