Wnt Antagonists Bind through a Short Peptide to the First β-Propeller Domain of LRP5/6

被引：147

作者：

Bourhis, Eric ^{[1
]}

Wang, Weiru ^{[2
]}

Tam, Christine ^{[2
]}

Hwang, Jiyoung ^{[2
]}

Zhang, Yingnan ^{[1
]}

Spittler, Didier ^{[1
]}

Huang, Oscar W. ^{[1
]}

Gong, Yan ^{[4
]}

Estevez, Alberto ^{[2
]}

Zilberleyb, Inna ^{[2
]}

Rouge, Lionel ^{[2
]}

Chiu, Cecilia ^{[3
]}

Wu, Yan ^{[3
]}

Costa, Mike ^{[4
]}

Hannoush, Rami N. ^{[1
]}

Franke, Yvonne ^{[2
]}

Cochran, Andrea G. ^{[1
]}

机构：

[1] Genentech Res & Early Dev, Dept Early Discovery Biochem, San Francisco, CA 94080 USA

[2] Genentech Res & Early Dev, Dept Struct Biol, San Francisco, CA 94080 USA

[3] Genentech Res & Early Dev, Dept Antibody Engn, San Francisco, CA 94080 USA

[4] Genentech Res & Early Dev, Canc Targets, San Francisco, CA 94080 USA

来源：

STRUCTURE | 2011年 / 19卷 / 10期

基金：

加拿大健康研究院; 美国国家卫生研究院; 加拿大自然科学与工程研究理事会;

关键词：

HIGH-BONE-MASS; SECRETED PROTEIN; RECEPTOR; SCLEROSTIN; INHIBITION; MECHANISM; DICKKOPF-1; MUTATIONS; DENSITY; LIGAND;

D O I：

10.1016/j.str.2011.07.005

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 Wnt pathway inhibitors DKK1 and sclerostin (SOST) are important therapeutic targets in diseases involving bone loss or damage. It has been appreciated that Wnt coreceptors LRP5/6 are also important, as human missense mutations that result in bone overgrowth (bone mineral density, or BMD, mutations) cluster to the El propeller domain of LRP5. Here, we report a crystal structure of LRP6 El bound to an antibody, revealing that the El domain is a peptide recognition module. Remarkably, the consensus El binding sequence is a close match to a conserved tripeptide motif present in all Wnt inhibitors that bind LRP5/6. We show that this motif is important for DKK1 and SOST binding to LRP6 and for inhibitory function, providing a detailed structural explanation for the effect of the BMD mutations.

引用

页码：1433 / 1442

页数：10

共 59 条

[1] Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling [J].

Ai, M ;

Holmen, SL ;

Van Hul, W ;

Williams, BO ;

Warman, ML .

MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (12) :4946-4955

[2] Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow [J].

Bafico, A ;

Liu, GZ ;

Yaniv, A ;

Gazit, A ;

Aaronson, SA .

NATURE CELL BIOLOGY, 2001, 3 (07) :683-686

[3] Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease [J].

Balemans, W ;

Patel, N ;

Ebeling, M ;

Van Hul, E ;

Wuyts, W ;

Lacza, C ;

Dioszegi, M ;

Dikkers, FG ;

Hildering, P ;

Willems, PJ ;

Verheij, JBGM ;

Lindpaintner, K ;

Vickery, B ;

Foernzler, D ;

Van Hul, W .

JOURNAL OF MEDICAL GENETICS, 2002, 39 (02) :91-97

[4] Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST) [J].

Balemans, W ;

Ebeling, M ;

Patel, N ;

Van Hul, E ;

Olson, P ;

Dioszegi, M ;

Lacza, C ;

Wuyts, W ;

Van den Ende, J ;

Willems, P ;

Paes-Alves, AF ;

Hill, S ;

Bueno, M ;

Ramos, FJ ;

Tacconi, P ;

Dikkers, FG ;

Stratakis, C ;

Lindpaintner, K ;

Vickery, B ;

Foernzler, D ;

Van Hul, W .

HUMAN MOLECULAR GENETICS, 2001, 10 (05) :537-543

[5] A new member of the frizzled family from Drosophila functions as a Wingless receptor [J].

Bhanot, P ;

Brink, M ;

Samos, CH ;

Hsieh, JC ;

Wang, YS ;

Macke, JP ;

Andrew, D ;

Nathans, J ;

Nusse, R .

NATURE, 1996, 382 (6588) :225-230

[6] Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation [J].

Bilic, Josipa ;

Huang, Ya-Lin ;

Davidson, Gary ;

Zimmermann, Timo ;

Cruciat, Cristina-Maria ;

Bienz, Mariann ;

Niehrs, Christof .

SCIENCE, 2007, 316 (5831) :1619-1622

[7] The First Propeller Domain of LRP6 Regulates Sensitivity to DKK1 [J].

Binnerts, Minke E. ;

Tomasevic, Nenad ;

Bright, Jessica M. ;

Leung, John ;

Ahn, Victoria E. ;

Kim, Kyung-Ah ;

Zhan, Xiaoming ;

Liu, Shouchun ;

Yonkovich, Shirlee ;

Williams, Jason ;

Zhou, Mei ;

Gros, Delphine ;

Dixon, Melissa ;

Korver, Wouter ;

Weis, William I. ;

Abo, Arie .

MOLECULAR BIOLOGY OF THE CELL, 2009, 20 (15) :3552-3560

[8] Reconstitution of a Frizzled8.Wnt3a.LRP6 Signaling Complex Reveals Multiple Wnt and Dkk1 Binding Sites on LRP6 [J].

Bourhis, Eric ;

Tam, Christine ;

Franke, Yvonne ;

Bazan, J. Fernando ;

Ernst, James ;

Hwang, Jiyoung ;

Costa, Mike ;

Cochran, Andrea G. ;

Hannoush, Rami N. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (12) :9172-9179

[9] High bone density due to a mutation in LDL-receptor-related protein 5 [J].

Boyden, LM ;

Mao, JH ;

Belsky, J ;

Mitzner, L ;

Farhi, A ;

Mitnick, MA ;

Wu, DQ ;

Insogna, K ;

Lifton, RP .

NEW ENGLAND JOURNAL OF MEDICINE, 2002, 346 (20) :1513-1521

[10] Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins [J].

Brott, BK ;

Sokol, SY .

MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (17) :6100-6110

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