A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking

Gopichandran Sowmya, Javed Mohammed Khan, Samyuktha Anand, Seong Beom Ahn, Mark S. Baker, Shoba Ranganathan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Integrin αvβ6 is an epithelially-restricted heterodimeric transmembrane glycoprotein, known to interact with the urokinase plasminogen activating receptor (uPAR), playing a critical role in cancer progression. While the X-ray crystallographic structures of segments of other integrin heterodimers are known, there is no structural information for the complete αvβ6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of αvβ6·uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the β-propeller region of integrin α-chain interacting with uPAR. Interaction of αvβ6·uPAR was demonstrated by our previous study using immunoprecipitation coupled with proteomic analysis by mass spectrometry. Recently this interaction was validated with proximity ligation assays and peptide arrays. The data suggested that two potential peptide regions from domain II and one peptide region from domain III of uPAR, interact with αvβ6 integrin. Only the peptide region from domain III is consistent with the three-dimensional interaction site proposed in this study. The molecular basis of integrin αvβ6·uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management.

LanguageEnglish
Pages327-335
Number of pages9
JournalJournal of Structural Biology
Volume185
Issue number3
DOIs
Publication statusPublished - Mar 2014

Fingerprint

Plasminogen
Urokinase-Type Plasminogen Activator
Integrins
Integrin alpha Chains
Immunoprecipitation
Proteomics
Ligation
Mass Spectrometry
Neoplasms
Glycoproteins
X-Rays
Peptides
Protein Domains

Cite this

@article{1b0c24bed50b44d0b2f1c5472aae2fd3,
title = "A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking",
abstract = "Integrin αvβ6 is an epithelially-restricted heterodimeric transmembrane glycoprotein, known to interact with the urokinase plasminogen activating receptor (uPAR), playing a critical role in cancer progression. While the X-ray crystallographic structures of segments of other integrin heterodimers are known, there is no structural information for the complete αvβ6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of αvβ6·uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the β-propeller region of integrin α-chain interacting with uPAR. Interaction of αvβ6·uPAR was demonstrated by our previous study using immunoprecipitation coupled with proteomic analysis by mass spectrometry. Recently this interaction was validated with proximity ligation assays and peptide arrays. The data suggested that two potential peptide regions from domain II and one peptide region from domain III of uPAR, interact with αvβ6 integrin. Only the peptide region from domain III is consistent with the three-dimensional interaction site proposed in this study. The molecular basis of integrin αvβ6·uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management.",
author = "Gopichandran Sowmya and Khan, {Javed Mohammed} and Samyuktha Anand and Ahn, {Seong Beom} and Baker, {Mark S.} and Shoba Ranganathan",
year = "2014",
month = "3",
doi = "10.1016/j.jsb.2014.01.001",
language = "English",
volume = "185",
pages = "327--335",
journal = "Journal of Structural Biology",
issn = "1047-8477",
publisher = "Academic Press Inc.",
number = "3",

}

A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking. / Sowmya, Gopichandran; Khan, Javed Mohammed; Anand, Samyuktha; Ahn, Seong Beom; Baker, Mark S.; Ranganathan, Shoba.

In: Journal of Structural Biology, Vol. 185, No. 3, 03.2014, p. 327-335.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking

AU - Sowmya, Gopichandran

AU - Khan, Javed Mohammed

AU - Anand, Samyuktha

AU - Ahn, Seong Beom

AU - Baker, Mark S.

AU - Ranganathan, Shoba

PY - 2014/3

Y1 - 2014/3

N2 - Integrin αvβ6 is an epithelially-restricted heterodimeric transmembrane glycoprotein, known to interact with the urokinase plasminogen activating receptor (uPAR), playing a critical role in cancer progression. While the X-ray crystallographic structures of segments of other integrin heterodimers are known, there is no structural information for the complete αvβ6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of αvβ6·uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the β-propeller region of integrin α-chain interacting with uPAR. Interaction of αvβ6·uPAR was demonstrated by our previous study using immunoprecipitation coupled with proteomic analysis by mass spectrometry. Recently this interaction was validated with proximity ligation assays and peptide arrays. The data suggested that two potential peptide regions from domain II and one peptide region from domain III of uPAR, interact with αvβ6 integrin. Only the peptide region from domain III is consistent with the three-dimensional interaction site proposed in this study. The molecular basis of integrin αvβ6·uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management.

AB - Integrin αvβ6 is an epithelially-restricted heterodimeric transmembrane glycoprotein, known to interact with the urokinase plasminogen activating receptor (uPAR), playing a critical role in cancer progression. While the X-ray crystallographic structures of segments of other integrin heterodimers are known, there is no structural information for the complete αvβ6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of αvβ6·uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the β-propeller region of integrin α-chain interacting with uPAR. Interaction of αvβ6·uPAR was demonstrated by our previous study using immunoprecipitation coupled with proteomic analysis by mass spectrometry. Recently this interaction was validated with proximity ligation assays and peptide arrays. The data suggested that two potential peptide regions from domain II and one peptide region from domain III of uPAR, interact with αvβ6 integrin. Only the peptide region from domain III is consistent with the three-dimensional interaction site proposed in this study. The molecular basis of integrin αvβ6·uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management.

UR - http://www.scopus.com/inward/record.url?scp=84894451766&partnerID=8YFLogxK

U2 - 10.1016/j.jsb.2014.01.001

DO - 10.1016/j.jsb.2014.01.001

M3 - Article

VL - 185

SP - 327

EP - 335

JO - Journal of Structural Biology

T2 - Journal of Structural Biology

JF - Journal of Structural Biology

SN - 1047-8477

IS - 3

ER -