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Allosteric network of dynamic coupling within BAP1-UCH revealed by methyl NMR

Chih-Hsuan Lai1, Yuan-Chao Lou2, Chi-Fon Chang3

  • 1Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.

Nature Communications
|May 26, 2026
PubMed

Insights

BRCA1-associated protein 1 (BAP1) mutations compromise its tumor-suppressing deubiquitinase (DUB) activity. Subtle structural changes disrupt BAP1

Area of Science:

  • Biochemistry
  • Structural Biology
  • Cancer Biology

Background:

  • BRCA1-associated protein 1 (BAP1) is a crucial tumor suppressor.
  • Its deubiquitinase (DUB) activity is vital for transcriptional regulation.
  • Cancer-associated mutations often affect the BAP1 ubiquitin carboxyl-terminal hydrolase (UCH) domain.

Purpose of the Study:

  • To elucidate the structural and dynamic mechanisms underlying oncogenic mutations in BAP1.
  • To map the effects of cancer mutations on BAP1-UCH methyl chemical shifts.
  • To understand how mutations disrupt BAP1's function and contribute to oncogenesis.

Main Methods:

  • Introduction of 22 cancer mutations and methyl mutations into the BAP1-UCH domain.
  • Analysis of methyl chemical shifts to map mutation effects.
  • Investigation of protein dynamics using NMR spectroscopy (implied by chemical shifts).

Main Results:

  • Identification of an allosteric coupling network centered on a conserved leucine (L49).
  • A specific mutation (L49V) abolished DUB activity by disrupting correlated motions.
  • Disruption of a phenylalanine cluster's concerted motions within the L49 hub.

Conclusions:

  • BAP1-UCH relies on a finely tuned dynamic network for its catalytic activity.
  • Minor structural alterations can destabilize this network, leading to loss of function.
  • Provides a mechanistic link between BAP1 mutations, disrupted dynamics, and cancer development.

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