Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Syed M. Moin, Sinisa Urban

Research output: Contribution to journalArticle

Abstract

Rhomboid proteases reside within cellular membranes, but the advantage of this unusual environment is unclear. We discovered membrane immersion allows substrates to be identified in a fundamentally-different way, based initially upon exposing 'masked' conformational dynamics of transmembrane segments rather than sequence-specific binding. EPR and CD spectroscopy revealed that the membrane restrains rhomboid gate and substrate conformation to limit proteolysis. True substrates evolved intrinsically-unstable transmembrane helices that both become unstructured when not supported by the membrane, and facilitate partitioning into the hydrophilic, active-site environment. Accordingly, manipulating substrate and gate dynamics in living cells shifted cleavage sites in a manner incompatible with extended sequence binding, but correlated with a membrane-and-helix-exit propensity scale. Moreover, cleavage of diverse non-substrates was provoked by single-residue changes that destabilize transmembrane helices. Membrane immersion thus bestows rhomboid proteases with the ability to identify substrates primarily based on reading their intrinsic transmembrane dynamics.

Original languageEnglish (US)
Article numbere00173
JournaleLife
Volume2012
Issue number1
DOIs
StatePublished - Nov 13 2012

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Immersion
Reading
Peptide Hydrolases
Membranes
Substrates
Proteolysis
Paramagnetic resonance
Conformations
Catalytic Domain
Spectrum Analysis
Cells
Spectroscopy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics. / Moin, Syed M.; Urban, Sinisa.

In: eLife, Vol. 2012, No. 1, e00173, 13.11.2012.

Research output: Contribution to journalArticle

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