Premium
Molecular and structural characterization of a TEAD mutation at the origin of Sveinsson's chorioretinal atrophy
Author(s) -
Bokhovchuk Fedir,
Mesrouze Yannick,
Izaac Aude,
Meyerhofer Marco,
Zimmermann Catherine,
Fontana Patrizia,
Schmelzle Tobias,
Erdmann Dirk,
Furet Pascal,
Kallen Joerg,
Chène Patrick
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14817
Subject(s) - protein data bank (rcsb pdb) , mutant , hippo signaling pathway , mutation , protein data bank , transcription factor , biology , genetics , sequence alignment , protein structure , gene , peptide sequence , biochemistry
Four TEAD transcription factors ( TEAD 1–4) mediate the signalling output of the Hippo pathway that controls organ size in humans. TEAD transcriptional activity is regulated via interactions with the YAP , TAZ and VGLL proteins. A mutation in the TEAD 1 gene, Tyr421His, has been identified in patients suffering from Sveinsson's chorioretinal atrophy ( SCA ), an autosomal dominant eye disease. This mutation prevents the YAP / TAZ : TEAD 1 interaction. In this study, we measure the affinity of YAP , TAZ and VGLL 1 for the four human TEAD s and find that they have a similar affinity for all TEAD s. We quantitate the effect of the mutation found in SCA patients and show that it destabilizes the YAP / TAZ : TEAD interaction by about 3 kcal·mol −1 . We determine the structure of YAP in complex with this mutant form of TEAD and show that the histidine residue adopts different conformations at the binding interface. The presence of this flexible residue induces the destabilization of several H‐bonds and the loss of van der Waals contacts, which explains why the Tyr421His TEAD 1 mutation has such a large destabilizing effect on the formation of the YAP : TEAD complex. Database The crystallographic data have been deposited at the RSCB Protein Data Bank (PDB, www.pdb.org ) with the access codes: 6HIL (wt YAP :Tyr421His TEAD1 ), 6HIK (wt YAP :Tyr429His TEAD4 )