Structure of the Human Cation-Independent Mannose 6-Phosphate/IGF2 Receptor Domains 7-11 Uncovers the Mannose 6-Phosphate Binding Site of Domain 9

被引：11

作者：

Bochel, Alice J. ^{[1
]}

Williams, Christopher ^{[1
]}

McCoy, Airlie J. ^{[2
]}

Hoppe, Hans-Jurgen ^{[3
,7
]}

Winter, Ashley J. ^{[1
]}

Nicholls, Ryan D. ^{[1
]}

Harlos, Karl ^{[4
]}

Jones, E. Yvonne ^{[4
]}

Berger, Imre ^{[5
]}

Hassan, A. Bassim ^{[3
]}

Crump, Matthew P. ^{[1
,6
]}

机构：

[1] Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England

[2] Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Keith Peters Bldg,Hills Rd, Cambridge CB2 0XY, England

[3] Univ Oxford, Sir William Dunn Sch Pathol, Oxford Mol Pathol Inst, Tumour Growth Control Grp, Oxford OX1 3RE, England

[4] Univ Oxford, Wellcome Ctr Human Genet, Div Struct Biol, Canc Res UK Receptor Struct Res Grp, Oxford OX3 7BN, England

[5] Univ Bristol, Sch Biochem, Bristol BS8 1TD, Avon, England

[6] BrisSynBio, Life Sci Bldg,Tyndall Ave, Bristol BS8 1TQ, Avon, England

[7] dAlnomics Ltd, 66 High St, Bassingbourn Royston SG8 5LF, England

来源：

STRUCTURE | 2020年 / 28卷 / 12期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

CI-MPR; domain; 9; IGF2R; mannose; 6-phosphate; P-type lectin; X-ray crystallography;

D O I：

10.1016/j.str.2020.08.002

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 cation-independent mannose 6-phosphate (M6P)/Insulin-like growth factor-2 receptor (CI-MPR/IGF2R) is an similar to 300 kDa transmembrane protein responsible for trafficking M6P-tagged lysosomal hydrolases and internalizing IGF2. The extracellular region of the CI-MPR has 15 homologous domains, including M6P-binding domains (D) 3, 5, 9, and 15 and IGF2-binding domain 11. We have focused on solving the first structures of human D7-10 within two multi- domain constructs, D9-10 and D7-11, and provide the first high-resolution description of the high-affinity M6P-binding D9. Moreover, D9 stabilizes a well-defined hub formed by D7-11 whereby two penta-domains intertwine to form a dimeric helical-type coil via an N-glycan bridge on D9. Remarkably the D7-11 structure matches an IGF2-bound state of the receptor, suggesting this may be an intrinsically stable conformation at neutral pH. Interdomain clusters of histidine and proline residues may impart receptor rigidity and play a role in structural transitions at low pH.

引用

页码：1300 / +

页数：18

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