Functional Elements on SIRPα IgV Domain Mediate Cell Surface Binding to CD47

Yuan Liu, Qiao Tong, Yubin Zhou, Hsiau-Wei Lee, Jenny J. Yang, Hans-Jörg Bühring, Yi-Tien Chen, Binh Ha, Celia X.-J. Chen, Yang Yang, Ke Zen

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

SIRPα and SIRPβ1, the two major isoforms of the signal regulatory protein (SIRP) family, are co-expressed in human leukocytes but mediate distinct extracellular binding interactions and divergent cell signaling responses. Previous studies have demonstrated that binding of SIRPα with CD47, another important cell surface molecule, through the extracellular IgV domain regulates important leukocyte functions including macrophage recognition, leukocyte adhesion and transmigration. Although SIRPβ1 shares highly homologous extracellular IgV structure with SIRPα, it does not bind to CD47. Here, we defined key amino acid residues exclusively expressing in the IgV domain of SIRPα, but not SIRPβ1, which determine the extracellular binding interaction of SIRPα to CD47. These key residues include Gln67, a small hydrophobic amino acid (Ala or Val) at the 57th position and Met102. We found that Gln67 and Ala/Val57 are critical. Mutation of either of these residues abates SIRPα directly binding to CD47. Functional cell adhesion and leukocyte transmigration assays further demonstrated central roles of Gln67 and Ala/Val57 in SIRPα extracellular binding mediated cell interactions and cell migration. Another SIRPα-specific residue, Met102, appears to assist SIRPα IgV binding through Gln67 and Ala/Val57. An essential role of these amino acid residues in SIRPα binding to CD47 was further confirmed by introducing these residues into the SIRPβ1 IgV domain, which dramatically converts SIRPβ1 into a CD47-binding molecule. Our results thus revealed the molecular basis by which SIRPα binds to CD47 and shed new light into the structural mechanisms of SIRP isoform mediated distinctive extracellular interactions and cellular responses.
Original languageTraditional Chinese
Pages (from-to)680-693
Number of pages14
JournalJournal of Molecular Biology
Volume365
Issue number3
DOIs
Publication statusPublished - 2007
Externally publishedYes

Cite this

Liu, Y., Tong, Q., Zhou, Y., Lee, H-W., Yang, J. J., Bühring, H-J., ... Zen, K. (2007). Functional Elements on SIRPα IgV Domain Mediate Cell Surface Binding to CD47. Journal of Molecular Biology, 365(3), 680-693. https://doi.org/10.1016/j.jmb.2006.09.079

Functional Elements on SIRPα IgV Domain Mediate Cell Surface Binding to CD47. / Liu, Yuan; Tong, Qiao; Zhou, Yubin; Lee, Hsiau-Wei; Yang, Jenny J.; Bühring, Hans-Jörg; Chen, Yi-Tien; Ha, Binh; Chen, Celia X.-J.; Yang, Yang; Zen, Ke.

In: Journal of Molecular Biology, Vol. 365, No. 3, 2007, p. 680-693.

Research output: Contribution to journalArticle

Liu, Y, Tong, Q, Zhou, Y, Lee, H-W, Yang, JJ, Bühring, H-J, Chen, Y-T, Ha, B, Chen, CX-J, Yang, Y & Zen, K 2007, 'Functional Elements on SIRPα IgV Domain Mediate Cell Surface Binding to CD47', Journal of Molecular Biology, vol. 365, no. 3, pp. 680-693. https://doi.org/10.1016/j.jmb.2006.09.079
Liu, Yuan ; Tong, Qiao ; Zhou, Yubin ; Lee, Hsiau-Wei ; Yang, Jenny J. ; Bühring, Hans-Jörg ; Chen, Yi-Tien ; Ha, Binh ; Chen, Celia X.-J. ; Yang, Yang ; Zen, Ke. / Functional Elements on SIRPα IgV Domain Mediate Cell Surface Binding to CD47. In: Journal of Molecular Biology. 2007 ; Vol. 365, No. 3. pp. 680-693.
@article{0f81d40b02dc4cf3a78b5f86a0c5cc5d,
title = "Functional Elements on SIRPα IgV Domain Mediate Cell Surface Binding to CD47",
abstract = "SIRPα and SIRPβ1, the two major isoforms of the signal regulatory protein (SIRP) family, are co-expressed in human leukocytes but mediate distinct extracellular binding interactions and divergent cell signaling responses. Previous studies have demonstrated that binding of SIRPα with CD47, another important cell surface molecule, through the extracellular IgV domain regulates important leukocyte functions including macrophage recognition, leukocyte adhesion and transmigration. Although SIRPβ1 shares highly homologous extracellular IgV structure with SIRPα, it does not bind to CD47. Here, we defined key amino acid residues exclusively expressing in the IgV domain of SIRPα, but not SIRPβ1, which determine the extracellular binding interaction of SIRPα to CD47. These key residues include Gln67, a small hydrophobic amino acid (Ala or Val) at the 57th position and Met102. We found that Gln67 and Ala/Val57 are critical. Mutation of either of these residues abates SIRPα directly binding to CD47. Functional cell adhesion and leukocyte transmigration assays further demonstrated central roles of Gln67 and Ala/Val57 in SIRPα extracellular binding mediated cell interactions and cell migration. Another SIRPα-specific residue, Met102, appears to assist SIRPα IgV binding through Gln67 and Ala/Val57. An essential role of these amino acid residues in SIRPα binding to CD47 was further confirmed by introducing these residues into the SIRPβ1 IgV domain, which dramatically converts SIRPβ1 into a CD47-binding molecule. Our results thus revealed the molecular basis by which SIRPα binds to CD47 and shed new light into the structural mechanisms of SIRP isoform mediated distinctive extracellular interactions and cellular responses.",
keywords = "Ig superfamily protein, signal regulatory proteins, IgV domain, extracellular binding interaction",
author = "Yuan Liu and Qiao Tong and Yubin Zhou and Hsiau-Wei Lee and Yang, {Jenny J.} and Hans-J{\"o}rg B{\"u}hring and Yi-Tien Chen and Binh Ha and Chen, {Celia X.-J.} and Yang Yang and Ke Zen",
year = "2007",
doi = "10.1016/j.jmb.2006.09.079",
language = "繁體中文",
volume = "365",
pages = "680--693",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Functional Elements on SIRPα IgV Domain Mediate Cell Surface Binding to CD47

AU - Liu, Yuan

AU - Tong, Qiao

AU - Zhou, Yubin

AU - Lee, Hsiau-Wei

AU - Yang, Jenny J.

AU - Bühring, Hans-Jörg

AU - Chen, Yi-Tien

AU - Ha, Binh

AU - Chen, Celia X.-J.

AU - Yang, Yang

AU - Zen, Ke

PY - 2007

Y1 - 2007

N2 - SIRPα and SIRPβ1, the two major isoforms of the signal regulatory protein (SIRP) family, are co-expressed in human leukocytes but mediate distinct extracellular binding interactions and divergent cell signaling responses. Previous studies have demonstrated that binding of SIRPα with CD47, another important cell surface molecule, through the extracellular IgV domain regulates important leukocyte functions including macrophage recognition, leukocyte adhesion and transmigration. Although SIRPβ1 shares highly homologous extracellular IgV structure with SIRPα, it does not bind to CD47. Here, we defined key amino acid residues exclusively expressing in the IgV domain of SIRPα, but not SIRPβ1, which determine the extracellular binding interaction of SIRPα to CD47. These key residues include Gln67, a small hydrophobic amino acid (Ala or Val) at the 57th position and Met102. We found that Gln67 and Ala/Val57 are critical. Mutation of either of these residues abates SIRPα directly binding to CD47. Functional cell adhesion and leukocyte transmigration assays further demonstrated central roles of Gln67 and Ala/Val57 in SIRPα extracellular binding mediated cell interactions and cell migration. Another SIRPα-specific residue, Met102, appears to assist SIRPα IgV binding through Gln67 and Ala/Val57. An essential role of these amino acid residues in SIRPα binding to CD47 was further confirmed by introducing these residues into the SIRPβ1 IgV domain, which dramatically converts SIRPβ1 into a CD47-binding molecule. Our results thus revealed the molecular basis by which SIRPα binds to CD47 and shed new light into the structural mechanisms of SIRP isoform mediated distinctive extracellular interactions and cellular responses.

AB - SIRPα and SIRPβ1, the two major isoforms of the signal regulatory protein (SIRP) family, are co-expressed in human leukocytes but mediate distinct extracellular binding interactions and divergent cell signaling responses. Previous studies have demonstrated that binding of SIRPα with CD47, another important cell surface molecule, through the extracellular IgV domain regulates important leukocyte functions including macrophage recognition, leukocyte adhesion and transmigration. Although SIRPβ1 shares highly homologous extracellular IgV structure with SIRPα, it does not bind to CD47. Here, we defined key amino acid residues exclusively expressing in the IgV domain of SIRPα, but not SIRPβ1, which determine the extracellular binding interaction of SIRPα to CD47. These key residues include Gln67, a small hydrophobic amino acid (Ala or Val) at the 57th position and Met102. We found that Gln67 and Ala/Val57 are critical. Mutation of either of these residues abates SIRPα directly binding to CD47. Functional cell adhesion and leukocyte transmigration assays further demonstrated central roles of Gln67 and Ala/Val57 in SIRPα extracellular binding mediated cell interactions and cell migration. Another SIRPα-specific residue, Met102, appears to assist SIRPα IgV binding through Gln67 and Ala/Val57. An essential role of these amino acid residues in SIRPα binding to CD47 was further confirmed by introducing these residues into the SIRPβ1 IgV domain, which dramatically converts SIRPβ1 into a CD47-binding molecule. Our results thus revealed the molecular basis by which SIRPα binds to CD47 and shed new light into the structural mechanisms of SIRP isoform mediated distinctive extracellular interactions and cellular responses.

KW - Ig superfamily protein

KW - signal regulatory proteins

KW - IgV domain

KW - extracellular binding interaction

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-33845804747&origin=resultslist&sort=plf-f&src=s&sid=d27753394ed3f6961a0045060437c57e&sot=autdocs&sdt=autdocs&sl=18&s=AU-ID%2835204610100%29&relpos=6&citeCnt=30&searchTerm=

UR - http://Functional Elements on SIRPα IgV Domain Mediate Cell Surface Binding to CD47

U2 - 10.1016/j.jmb.2006.09.079

DO - 10.1016/j.jmb.2006.09.079

M3 - 文章

VL - 365

SP - 680

EP - 693

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 3

ER -