Dataset Information

Structural basis for autoinhibition and its relief of MOB1 in the Hippo pathway.

ABSTRACT: MOB1 protein is a key regulator of large tumor suppressor 1/2 (LATS1/2) kinases in the Hippo pathway. MOB1 is present in an autoinhibited form and is activated by MST1/2-mediated phosphorylation, although the precise mechanisms responsible for autoinhibition and activation are unknown due to lack of an autoinhibited MOB1 structure. Here, we report on the crystal structure of full-length MOB1B in the autoinhibited form and a complex between the MOB1B core domain and the N-terminal regulation (NTR) domain of LATS1. The structure of full-length MOB1B shows that the N-terminal extension forms a short ?-strand, the SN strand, followed by a long conformationally flexible positively-charged linker and ?-helix, the Switch helix, which blocks the LATS1 binding surface of MOB1B. The Switch helix is stabilized by ?-sheet formation of the SN strand with the S2 strand of the MOB1 core domain. Phosphorylation of Thr12 and Thr35 residues structurally accelerates dissociation of the Switch helix from the LATS1-binding surface by the "pull-the-string" mechanism, thereby enabling LATS1 binding.

SUBMITTER: Kim SY

PROVIDER: S-EPMC4917820 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structural basis for autoinhibition and its relief of MOB1 in the Hippo pathway.

Kim Sun-Yong SY Tachioka Yuka Y Mori Tomoyuki T Hakoshima Toshio T

Scientific reports 20160623

MOB1 protein is a key regulator of large tumor suppressor 1/2 (LATS1/2) kinases in the Hippo pathway. MOB1 is present in an autoinhibited form and is activated by MST1/2-mediated phosphorylation, although the precise mechanisms responsible for autoinhibition and activation are unknown due to lack of an autoinhibited MOB1 structure. Here, we report on the crystal structure of full-length MOB1B in the autoinhibited form and a complex between the MOB1B core domain and the N-terminal regulation (NTR ...[more]

PMID: 27335147

Similar Datasets

Project description:The Hippo tumor suppressor pathway regulates organ size and tissue homoeostasis in response to diverse signaling inputs. The core of the pathway consists of a short kinase cascade: MST1 and MST2 phosphorylate and activate LATS1 and LATS2, which in turn phosphorylate and inactivate key transcriptional coactivators, YAP1 and TAZ (gene WWTR1). The MOB1 adapter protein regulates both phosphorylation reactions firstly by concurrently binding to the upstream MST and downstream LATS kinases to enable the trans phosphorylation reaction, and secondly by allosterically activating the catalytic function of LATS1 and LATS2 to directly stimulate phosphorylation of YAP and TAZ. Studies of yeast Mob1 and human MOB1 revealed that the ability to recognize phosphopeptide sequences in their interactors, Nud1 and MST2 respectively, was critical to their roles in regulating the Mitotic Exit Network in yeast and the Hippo pathway in metazoans. However, the underlying rules of phosphopeptide recognition by human MOB1, the implications of binding specificity for Hippo pathway signaling, and the generality of phosphopeptide binding function to other human MOB family members remained elusive.Employing proteomics, peptide arrays and biochemical analyses, we systematically examine the phosphopeptide binding specificity of MOB1 and find it to be highly complementary to the substrate phosphorylation specificity of MST1 and MST2. We demonstrate that autophosphorylation of MST1 and MST2 on several threonine residues provides multiple MOB1 binding sites with varying binding affinities which in turn contribute to a redundancy of MST1-MOB1 protein interactions in cells. The crystal structures of MOB1A in complex with two favored phosphopeptide sites in MST1 allow for a full description of the MOB1A phosphopeptide-binding consensus. Lastly, we show that the phosphopeptide binding properties of MOB1A are conserved in all but one of the seven MOB family members in humans, thus providing a starting point for uncovering their elusive cellular functions.

Dataset Information

Structural basis for autoinhibition and its relief of MOB1 in the Hippo pathway.

Publications

Structural basis for autoinhibition and its relief of MOB1 in the Hippo pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets