Research Papers:

Biophysical studies and NMR structure of YAP2 WW domain - LATS1 PPxY motif complexes reveal the basis of their interaction

Apoorva Verma _, Fan Jing-Song, Megan L. Finch-Edmondson, Adrian Velazquez-Campoy, Shanker Balasegaran, J. Sivaraman Sivaraman and Jayaraman Sivaraman

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Oncotarget. 2018; 9:8068-8080. https://doi.org/10.18632/oncotarget.23909

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Apoorva Verma1, Fan Jing-Song1, Megan L. Finch-Edmondson2, Adrian Velazquez-Campoy3, Shanker Balasegaran1, Marius Sudol2,4,5 and Jayaraman Sivaraman1

1Department of Biological Sciences, National University of Singapore, Singapore

2Mechanobiology Institute, National University of Singapore, Singapore

3Institute of Biocomputation and Physics of Complex Systems (BIFI)–Joint Units: BIFI–IQFR (CSIC) and GBsC–CSIC, Universidad de Zaragoza, Spain, Department of Biochemistry and Molecular and Cellular Biology, Universidad de Zaragoza, Fundacion ARAID, Gobierno de Aragon, Spain, Aragon Health Research Institute (IIS Aragon), Universidad de Zaragoza, Zaragoza, Spain

4Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9, Singapore

5Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research, Singapore

Correspondence to:

Jayaraman Sivaraman, email: dbsjayar@nus.edu.sg

Keywords: hippo pathway; YAP; LATS; WW domain; PPxY motif

Received: July 28, 2017     Accepted: November 05, 2017     Published: January 03, 2018


YES-associated protein (YAP) is a major effector protein of the Hippo tumor suppressor pathway, and is phosphorylated by the serine/threonine kinase LATS. Their binding is mediated by the interaction between WW domains of YAP and PPxY motifs of LATS. Their isoforms, YAP2 and LATS1 contain two WW domains and two PPxY motifs respectively. Here, we report the study of the interaction of these domains both in vitro and in human cell lines, to better understand the mechanism of their binding. We show that there is a reciprocal binding preference of YAP2-WW1 with LATS1-PPxY2, and YAP2-WW2 with LATS1-PPxY1. We solved the NMR structures of these complexes and identified several conserved residues that play a critical role in binding. We further created a YAP2 mutant by swapping the WW domains, and found that YAP2 phosphorylation at S127 by LATS1 is not affected by the spatial configuration of its WW domains. This is likely because the region between the PPxY motifs of LATS1 is unstructured, even upon binding with its partner. Based on our observations, we propose possible models for the interaction between YAP2 and LATS1.

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