Journal Article

FZJ-2018-01518

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The human platelet antigen-1b variant of $\alpha$$_{IIb}$β$_{3}$ allosterically shifts the dynamic conformational equilibrium of this integrin toward the active state

Pagani, G. ; Pereira, J. P. V. ; Stoldt, V. R. ; Beck, A. ; Scharf, R. E. ; Gohlke, H. (Corresponding author)FZJ*

2018
Soc. Bethesda, Md.

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Please use a persistent id in citations: http://hdl.handle.net/2128/18270  doi:10.1074/jbc.RA118.002149

Abstract: Integrins are heterodimeric cell-adhesion receptors comprising α and β subunits. The human platelet antigen-1 (HPA-1) polymorphism in αIIbβ3 arises from a Leu→Pro exchange at residue 33 in the genu of the β3 subunit, resulting in Leu-33 (HPA-1a) or Pro-33 (HPA-1b) isoforms. Although clinical investigations have provided conflicting results, some studies have suggested that Pro-33 platelets exhibit increased thrombogenicity. Under flow-dynamic conditions, the Pro-33 variant displays prothrombotic properties, characterized by increased platelet adhesion, aggregate/thrombus formation, and outside-in signaling. However, the molecular events underlying this prothrombotic phenotype have remained elusive. As residue 33 is located > 80 Å away from extracellular binding sites or transmembrane domains, we hypothesized that the Leu→Pro exchange allosterically shifts the dynamic conformational equilibrium of αIIbβ3 toward an active state. Multiple microsecond-long, all-atom molecular dynamics simulations of the ectodomain of the Leu-33 and Pro-33 isoforms provided evidence that the Leu→Pro exchange weakens interdomain interactions at the genu and alters the structural dynamics of the integrin to a more unbent and splayed state. Using FRET analysis of fluorescent proteins fused with αIIbβ3 in transfected HEK293 cells, we found that the Pro-33 variant in its resting state displays a lower energy transfer than the Leu-33 isoform. This finding indicated a larger spatial separation of the cytoplasmic tails in the Pro-33 variant. Together, our results indicate that the Leu→Pro exchange allosterically shifts the dynamic conformational equilibrium of αIIbβ3 to a structural state closer to the active one, promoting the fully active state and fostering the prothrombotic phenotype of Pro-33 platelets.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. Strukturbiochemie (ICS-6)

Research Program(s):

1. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)

Appears in the scientific report 2018

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Database coverage:
; ; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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