Basic amino-acid side chains regulate transmembrane integrin signalling

Chungho Kim, Thomas Schmidt, Eun Gyung Cho, Feng Ye, Tobias S. Ulmer, Mark H. Ginsberg

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Side chains of Lys/Arg near transmembrane domain (TMD) membrane-water interfaces can snorkel', placing their positive charge near negatively charged phospholipid head groups; however, snorkelling's functional effects are obscure. Integrin β TMDs have such conserved basic amino acids. Here we use NMR spectroscopy to show that integrin β 3 (Lys-716) helps determine β 3 TMD topography. The α IIb β 3 TMD structure indicates that precise β 3 TMD crossing angles enable the assembly of outer and inner membrane clasps' that hold the αβ TMD together to limit transmembrane signalling. Mutation of β 3 (Lys-716) caused dissociation of α IIb β 3 TMDs and integrin activation. To confirm that altered topography of β 3 (Lys-716) mutants activated α IIb β 3, we used directed evolution of β 3 (K716A) to identify substitutions restoring default state. Introduction of Pro(711) at the midpoint of β 3 TMD (A711P) increased α IIb β 3 TMD association and inactivated integrin α IIb β 3 (A711P,K716A). β 3 (Pro-711) introduced a TMD kink of 30-±-1° precisely at the border of the outer and inner membrane clasps, thereby decoupling the tilt between these segments. Thus, widely occurring snorkelling residues in TMDs can help maintain TMD topography and membrane-embedding, thereby regulating transmembrane signalling.

Original languageEnglish
Pages (from-to)209-214
Number of pages6
JournalNature
Volume481
Issue number7380
DOIs
Publication statusPublished - 2012 Jan 12
Externally publishedYes

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Basic Amino Acids
Integrins
Membranes
Phospholipids
Magnetic Resonance Spectroscopy
Mutation
Water

ASJC Scopus subject areas

  • General

Cite this

Kim, C., Schmidt, T., Cho, E. G., Ye, F., Ulmer, T. S., & Ginsberg, M. H. (2012). Basic amino-acid side chains regulate transmembrane integrin signalling. Nature, 481(7380), 209-214. https://doi.org/10.1038/nature10697

Basic amino-acid side chains regulate transmembrane integrin signalling. / Kim, Chungho; Schmidt, Thomas; Cho, Eun Gyung; Ye, Feng; Ulmer, Tobias S.; Ginsberg, Mark H.

In: Nature, Vol. 481, No. 7380, 12.01.2012, p. 209-214.

Research output: Contribution to journalArticle

Kim, C, Schmidt, T, Cho, EG, Ye, F, Ulmer, TS & Ginsberg, MH 2012, 'Basic amino-acid side chains regulate transmembrane integrin signalling', Nature, vol. 481, no. 7380, pp. 209-214. https://doi.org/10.1038/nature10697
Kim C, Schmidt T, Cho EG, Ye F, Ulmer TS, Ginsberg MH. Basic amino-acid side chains regulate transmembrane integrin signalling. Nature. 2012 Jan 12;481(7380):209-214. https://doi.org/10.1038/nature10697
Kim, Chungho ; Schmidt, Thomas ; Cho, Eun Gyung ; Ye, Feng ; Ulmer, Tobias S. ; Ginsberg, Mark H. / Basic amino-acid side chains regulate transmembrane integrin signalling. In: Nature. 2012 ; Vol. 481, No. 7380. pp. 209-214.
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