2. Academic Validation
  3. Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20

Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20

  • Mol Cell. 2016 Jul 21;63(2):249-260. doi: 10.1016/j.molcel.2016.05.031.
Heng Li 1,  Kah Suan Lim 2,  Hyungjin Kim 3,  Thomas R Hinds 4,  Ukhyun Jo 3,  Haibin Mao 1,  Caroline E Weller 5,  Ji Sun 4,  Champak Chatterjee 5,  Alan D D'Andrea 2,  Ning Zheng 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Box 357280, University of Washington, Seattle, WA 98195, USA.
  • 2 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
  • 4 Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • 5 Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
  • 6 Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Box 357280, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
PMID: 27373336 DOI: 10.1016/j.molcel.2016.05.031
Abstract

Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved Deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the Enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the Enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.

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