Structure
Volume 24, Issue 12, 6 December 2016, Pages 2152-2162
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Article
Structural Basis of Dimeric Rasip1 RA Domain Recognition of the Ras Subfamily of GTP-Binding Proteins

https://doi.org/10.1016/j.str.2016.10.001Get rights and content
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Highlights

  • We solved the crystal structure of Raisp1 RA domain (RRA) and in complex with Rap1

  • In contrast to most RA domains, RRA has an extended C terminus and forms a dimer

  • The RRA dimer can bind two Rap1 or Ras molecules (KD = 0.9 and 2.2 μM, respectively)

  • Rap1 binding via its switch I domain induces few conformation changes in RRA

Summary

Ras-interacting protein 1 (Rasip1) is an endothelial-specific Rap1 and Ras effector, important for vascular development and angiogenesis. Here, we report the crystal structure of the Rasip1 RA domain (RRA) alone, revealing the basis of dimerization, and in complex with Rap1 at 2.8 Å resolution. In contrast to most RA domains, RRA formed a dimer that can bind two Rap1 (KD = 0.9 μM) or Ras (KD = 2.2 μM) molecules. We solved the Rap1-RRA complex and found that Rasip1 binds Rap1 in the Switch I region, and Rap1 binding induces few conformation changes to Rasip1 stabilizing a β strand and an unstructured loop. Our data explain how Rasip1 can act as a Rap1 and Ras effector and show that Rasip1 defines a subgroup of dimeric RA domains that could mediate cooperative binding to membrane-associated Ras superfamily members.

Keywords

Ras-interacting protein 1 (Rasip1)
rain
Rap
Ras
Radil
Ras-association (RA) domain
dimer
crystal structure
GTP-binding proteins
heart of glass (HEG1)

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