Structural mechanism of laminin recognition by integrin.
Amino Acid Sequence
Basement Membrane
/ metabolism
Binding Sites
/ physiology
Cell Adhesion
/ physiology
Cryoelectron Microscopy
Crystallography, X-Ray
Epithelial Cells
/ metabolism
Humans
Integrin alpha6
/ metabolism
Integrin alpha6beta1
/ metabolism
Integrin beta1
/ metabolism
Laminin
/ metabolism
Protein Conformation
Protein Domains
/ physiology
Static Electricity
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 06 2021
29 06 2021
Historique:
received:
19
09
2020
accepted:
04
06
2021
entrez:
30
6
2021
pubmed:
1
7
2021
medline:
23
7
2021
Statut:
epublish
Résumé
Recognition of laminin by integrin receptors is central to the epithelial cell adhesion to basement membrane, but the structural background of this molecular interaction remained elusive. Here, we report the structures of the prototypic laminin receptor α6β1 integrin alone and in complex with three-chain laminin-511 fragment determined via crystallography and cryo-electron microscopy, respectively. The laminin-integrin interface is made up of several binding sites located on all five subunits, with the laminin γ1 chain C-terminal portion providing focal interaction using two carboxylate anchor points to bridge metal-ion dependent adhesion site of integrin β1 subunit and Asn189 of integrin α6 subunit. Laminin α5 chain also contributes to the affinity and specificity by making electrostatic interactions with large surface on the β-propeller domain of α6, part of which comprises an alternatively spliced X1 region. The propeller sheet corresponding to this region shows unusually high mobility, suggesting its unique role in ligand capture.
Identifiants
pubmed: 34188035
doi: 10.1038/s41467-021-24184-8
pii: 10.1038/s41467-021-24184-8
pmc: PMC8241838
doi:
Substances chimiques
Integrin alpha6
0
Integrin alpha6beta1
0
Integrin beta1
0
Laminin
0
laminin alpha5
0
laminin gamma 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4012Références
Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002).
pubmed: 12297042
doi: 10.1016/S0092-8674(02)00971-6
Brown, N. H. Cell-cell adhesion via the ECM: integrin genetics in fly and worm. Matrix Biol. 19, 191–201 (2000).
pubmed: 10936444
doi: 10.1016/S0945-053X(00)00064-0
Hynes, R. O. & Zhao, Q. The evolution of cell adhesion. J. Cell Biol. 150, F89–F96 (2000).
pubmed: 10908592
doi: 10.1083/jcb.150.2.F89
Pozzi, A. & Zent, R. Extracellular matrix receptors in branched organs. Curr. Opin. Cell. Biol. 23, 547–553 (2011).
pubmed: 21561755
pmcid: 3181278
doi: 10.1016/j.ceb.2011.04.003
Danen, E. H. & Sonnenberg, A. Integrins in regulation of tissue development and function. J. Pathol. 201, 632–641 (2003).
pubmed: 14648669
doi: 10.1002/path.1472
Aumailley, M. et al. A simplified laminin nomenclature. Matrix Biol. 24, 326–332 (2005).
pubmed: 15979864
doi: 10.1016/j.matbio.2005.05.006
Yamada, M. & Sekiguchi, K. Molecular basis of laminin-integrin interactions. Curr. Top. Membr. 76, 197–229 (2015).
pubmed: 26610915
doi: 10.1016/bs.ctm.2015.07.002
Hohenester, E. Structural biology of laminins. Essays Biochem 63, 285–295 (2019).
pubmed: 31092689
pmcid: 6744579
doi: 10.1042/EBC20180075
Shibata, S. et al. Selective laminin-directed differentiation of human induced pluripotent stem cells into distinct ocular lineages. Cell Rep. 25, 1668–1679 e1665 (2018).
pubmed: 30404017
doi: 10.1016/j.celrep.2018.10.032
Miner, J. H. & Yurchenco, P. D. Laminin functions in tissue morphogenesis. Annu. Rev. Cell. Dev. Biol. 20, 255–284 (2004).
pubmed: 15473841
doi: 10.1146/annurev.cellbio.20.010403.094555
Edgar, D., Timpl, R. & Thoenen, H. The heparin-binding domain of laminin is responsible for its effects on neurite outgrowth and neuronal survival. EMBO J. 3, 1463–1468 (1984).
pubmed: 6745238
pmcid: 557545
doi: 10.1002/j.1460-2075.1984.tb01997.x
Takizawa, M. et al. Mechanistic basis for the recognition of laminin-511 by alpha6beta1 integrin. Sci. Adv. 3, e1701497 (2017).
pubmed: 28879238
pmcid: 5580876
doi: 10.1126/sciadv.1701497
Pulido, D., Hussain, S. A. & Hohenester, E. Crystal Structure of the Heterotrimeric Integrin-Binding Region of Laminin-111. Structure 25, 530–535 (2017).
pubmed: 28132784
pmcid: 5343747
doi: 10.1016/j.str.2017.01.002
Nagae, M. et al. Crystal structure of alpha 5 beta 1 integrin ectodomain: Atomic details of the fibronectin receptor. J. Cell. Biol. 197, 131–140 (2012).
pubmed: 22451694
pmcid: 3317794
doi: 10.1083/jcb.201111077
Xiong, J. P. et al. Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science 296, 151–155 (2002).
pubmed: 11884718
doi: 10.1126/science.1069040
Springer, T. A., Zhu, J. & Xiao, T. Structural basis for distinctive recognition of fibrinogen gammaC peptide by the platelet integrin alphaIIbbeta3. J. Cell Biol. 182, 791–800 (2008).
pubmed: 18710925
pmcid: 2518716
doi: 10.1083/jcb.200801146
Dong, X., Hudson, N. E., Lu, C. & Springer, T. A. Structural determinants of integrin beta-subunit specificity for latent tgf-beta. Nat. Struct. Biol. 21, 1091–1096 (2014).
doi: 10.1038/nsmb.2905
Zhu, J. Q., Zhu, J. H. & Springer, T. A. Complete integrin headpiece opening in eight steps. J. Cell Biol. 201, 1053–1068 (2013).
pubmed: 23798730
pmcid: 3691460
doi: 10.1083/jcb.201212037
Takagi, J., Petre, B. M., Walz, T. & Springer, T. A. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110, 599–611 (2002).
pubmed: 12230977
doi: 10.1016/S0092-8674(02)00935-2
Campbell, I.D. & Humphries, M.J. Integrin structure, activation, and interactions. Cold Spring Harb. Perspect. Biol. 3 (2011).
Yu, Y. M. et al. Structural specializations of alpha(4)beta(7), an integrin that mediates rolling adhesion. J. Cell Biol. 196, 131–146 (2012).
pubmed: 22232704
pmcid: 3255974
doi: 10.1083/jcb.201110023
Nishida, N. et al. Activation of leukocyte beta2 integrins by conversion from bent to extended conformations. Immunity 25, 583–594 (2006).
pubmed: 17045822
doi: 10.1016/j.immuni.2006.07.016
Chen, X. et al. Requirement of open headpiece conformation for activation of leukocyte integrin alphaXbeta2. Proc. Natl Acad. Sci. USA 107, 14727–14732 (2010).
pubmed: 20679211
pmcid: 2930457
doi: 10.1073/pnas.1008663107
Xiao, T., Takagi, J., Coller, B. S., Wang, J. H. & Springer, T. A. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 432, 59–67 (2004).
pubmed: 15378069
pmcid: 4372090
doi: 10.1038/nature02976
Miyazaki, N., Iwasaki, K. & Takagi, J. A systematic survey of conformational states in beta1 and beta4 integrins using negative-stain electron microscopy. J. Cell Sci. 131 (2018).
Nishiuchi, R. et al. Ligand-binding specificities of laminin-binding integrins: a comprehensive survey of laminin-integrin interactions using recombinant alpha3beta1, alpha6beta1, alpha7beta1 and alpha6beta4 integrins. Matrix Biol. 25, 189–197 (2006).
pubmed: 16413178
doi: 10.1016/j.matbio.2005.12.001
Hemler, M. E., Crouse, C. & Sonnenberg, A. Association of the VLA alpha 6 subunit with a novel protein. A possible alternative to the common VLA beta 1 subunit on certain cell lines. J. Biol. Chem. 264, 6529–6235 (1989).
pubmed: 2649503
doi: 10.1016/S0021-9258(18)83380-4
Shen, Q. et al. Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3, 289–300 (2008).
pubmed: 18786416
pmcid: 2747473
doi: 10.1016/j.stem.2008.07.026
Yang, Z. et al. CD49f acts as an inflammation sensor to regulate differentiation, adhesion, and migration of human mesenchymal. Stem Cells Stem Cells 33, 2798–2810 (2015).
pubmed: 26013602
doi: 10.1002/stem.2063
Villa-Diaz, L. G., Kim, J. K., Laperle, A., Palecek, S. P. & Krebsbach, P. H. Inhibition of focal adhesion kinase signaling by integrin alpha6beta1 supports human pluripotent stem cell self-renewal. Stem Cells 34, 1753–1764 (2016).
pubmed: 26930028
doi: 10.1002/stem.2349
Toya, S. P. et al. Integrin alpha6beta1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells. Stem Cells 33, 1719–1729 (2015).
pubmed: 25693840
pmcid: 4441581
doi: 10.1002/stem.1974
Miyazaki, T. et al. Laminin e8 fragments support efficient adhesion and expansion of dissociated human pluripotent stem cells. Nat. Commun. 3 (2012).
Krebsbach, P. H. & Villa-Diaz, L. G. The role of integrin alpha6 (CD49f) in stem cells: more than a conserved biomarker. Stem Cells Dev. 26, 1090–1099 (2017).
pubmed: 28494695
pmcid: 5563922
doi: 10.1089/scd.2016.0319
Zhou, Z. et al. alpha6-Integrin alternative splicing: distinct cytoplasmic variants in stem cell fate specification and niche interaction. Stem Cell Res. Ther. 9, 122 (2018).
pubmed: 29720266
pmcid: 5930856
doi: 10.1186/s13287-018-0868-3
Arimori, T. et al. Fv-clasp: an artificially designed small antibody fragment with improved production compatibility, stability, and crystallizability. Structure 25, 1611–1622 e1614 (2017).
pubmed: 28919443
doi: 10.1016/j.str.2017.08.011
Xia, W. & Springer, T. A. Metal ion and ligand binding of integrin alpha5beta1. Proc. Natl Acad. Sci. USA 111, 17863–17868 (2014).
pubmed: 25475857
pmcid: 4273411
doi: 10.1073/pnas.1420645111
de Melker, A. A. & Sonnenberg, A. Integrins: alternative splicing as a mechanism to regulate ligand binding and integrin signaling events. Bioessays 21, 499–509 (1999).
pubmed: 10402956
doi: 10.1002/(SICI)1521-1878(199906)21:6<499::AID-BIES6>3.0.CO;2-D
Luo, B. H., Strokovich, K., Walz, T., Springer, T. A. & Takagi, J. Allosteric beta1 integrin antibodies that stabilize the low affinity state by preventing the swing-out of the hybrid domain. J. Biol. Chem. 279, 27466–27471 (2004).
pubmed: 15123676
doi: 10.1074/jbc.M404354200
Su, Y. et al. Relating conformation to function in integrin alpha5beta1. Proc. Natl Acad. Sci. USA. 113, E3872–E3881 (2016).
pubmed: 27317747
pmcid: 4941492
doi: 10.1073/pnas.1605074113
Luque, A. et al. Activated conformations of very late activation integrins detected by a group of antibodies (HUTS) specific for a novel regulatory region (355-425) of the common beta 1 chain. J. Biol. Chem. 271, 11067–11075 (1996).
pubmed: 8626649
doi: 10.1074/jbc.271.19.11067
Takagi, J., Strokovich, K., Springer, T. A. & Walz, T. Structure of integrin alpha5beta1 in complex with fibronectin. EMBO J. 22, 4607–4615 (2003).
pubmed: 12970173
pmcid: 212714
doi: 10.1093/emboj/cdg445
Eng, E. T., Smagghe, B. J., Walz, T. & Springer, T. A. Intact alpha(IIb)beta(3) integrin is extended after activation as measured by solution x-ray scattering and electron microscopy. J. Biol. Chem. 286, 35218–35226 (2011).
pubmed: 21832081
pmcid: 3186426
doi: 10.1074/jbc.M111.275107
Dong, X. et al. Force interacts with macromolecular structure in activation of TGF-beta. Nature 542, 55–59 (2017).
pubmed: 28117447
pmcid: 5586147
doi: 10.1038/nature21035
Wang, J. et al. Atypical interactions of integrin alphaVbeta8 with pro-TGF-beta1. Proc. Natl Acad. Sci. USA 114, E4168–E4174 (2017).
pubmed: 28484027
pmcid: 5448207
Mould, A. P. et al. Conformational changes in the integrin beta A domain provide a mechanism for signal transduction via hybrid domain movement. J. Biol. Chem. 278, 17028–17035 (2003).
pubmed: 12615914
doi: 10.1074/jbc.M213139200
Ido, H. et al. The requirement of the glutamic acid residue at the third position from the carboxyl termini of the laminin gamma chains in integrin binding by laminins. J. Biol. Chem. 282, 11144–11154 (2007).
pubmed: 17307733
doi: 10.1074/jbc.M609402200
Nesic, D. et al. Cryo-electron microscopy structure of the alphaiibbeta3-abciximab complex. Arterioscler. Thromb. Vasc. Biol. 40, 624–637 (2020).
pubmed: 31969014
pmcid: 7047619
doi: 10.1161/ATVBAHA.119.313671
Campbell, M. G. et al. Cryo-EM reveals integrin-mediated TGF-beta activation without release from latent TGF-beta. Cell 180, 490–501 e416 (2020).
pubmed: 31955848
pmcid: 7238552
doi: 10.1016/j.cell.2019.12.030
Wang, J., Su, Y., Iacob, R. E., Engen, J. R. & Springer, T. A. General structural features that regulate integrin affinity revealed by atypical alphaVbeta8. Nat. Commun. 10, 5481 (2019).
pubmed: 31792290
pmcid: 6889490
doi: 10.1038/s41467-019-13248-5
Lin, F. Y., Zhu, J., Eng, E. T., Hudson, N. E. & Springer, T. A. beta-Subunit Binding Is Sufficient for Ligands to Open the Integrin alphaIIbbeta3 Headpiece. J. Biol. Chem. 291, 4537–4546 (2016).
pubmed: 26631735
doi: 10.1074/jbc.M115.705624
Sen, M., Yuki, K. & Springer, T. A. An internal ligand-bound, metastable state of a leukocyte integrin, alpha(X)beta(2). J. Cell Biol. 203, 629–642 (2013).
pubmed: 24385486
pmcid: 3840939
doi: 10.1083/jcb.201308083
Takagi, J. & Springer, T. A. Integrin activation and structural rearrangement. Immunological Rev. 186, 141–163 (2002).
doi: 10.1034/j.1600-065X.2002.18613.x
Kamata, T., Tieu, K. K., Irie, A., Springer, T. A. & Takada, Y. Amino acid residues in the alpha IIb subunit that are critical for ligand binding to integrin alpha IIbbeta 3 are clustered in the beta-propeller model. J. Biol. Chem. 276, 44275–44283 (2001).
pubmed: 11557768
doi: 10.1074/jbc.M107021200
von der Mark, H. et al. Alternative splice variants of alpha 7 beta 1 integrin selectively recognize different laminin isoforms. J. Biol. Chem. 277, 6012–6016 (2002).
pubmed: 11744715
doi: 10.1074/jbc.M102188200
Delwel, G. O., Kuikman, I. & Sonnenberg, A. An alternatively spliced exon in the extracellular domain of the human alpha 6 integrin subunit—functional analysis of the alpha 6 integrin variants. Cell Adhes. Commun. 3, 143–161 (1995).
pubmed: 7583007
doi: 10.3109/15419069509081283
Taniguchi, Y., Takizawa, M., Li, S. & Sekiguchi, K. Bipartite mechanism for laminin-integrin interactions: Identification of the integrin-binding site in lg domains of the laminin alpha chain. Matrix Biol. 87, 66–76 (2020).
pubmed: 31669520
doi: 10.1016/j.matbio.2019.10.005
Pierschbacher, M. D. & Ruoslahti, E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 309, 30–33 (1984).
pubmed: 6325925
doi: 10.1038/309030a0
Kabsch, W.Xds. Acta Crystallogr. D. Biol. Crystallogr. 66, 125–132 (2010).
pubmed: 20124692
pmcid: 2815665
doi: 10.1107/S0907444909047337
Mccoy, A. J. et al. Phaser crystallographic software. J. Appl. Cryst. 40, 658–674 (2007).
doi: 10.1107/S0021889807021206
Winn, M. D. et al. Overview of the CCP4 suite and current developments. Acta Crystallogr. D. Biol. Crystallogr. 67, 235–242 (2011).
pubmed: 21460441
pmcid: 3069738
doi: 10.1107/S0907444910045749
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D. Biol. Crystallogr. 66, 213–221 (2010).
pubmed: 20124702
pmcid: 2815670
doi: 10.1107/S0907444909052925
Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D. Biol. Crystallogr. 66, 486–501 (2010).
pubmed: 20383002
pmcid: 2852313
doi: 10.1107/S0907444910007493
Kato, K. et al. Structure of a cyanobacterial photosystem I tetramer revealed by cryo-electron microscopy. Nat. Commun. 10, 4929 (2019).
pubmed: 31666526
pmcid: 6821847
doi: 10.1038/s41467-019-12942-8
Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).
pubmed: 28250466
pmcid: 5494038
doi: 10.1038/nmeth.4193
Zhang, K. Gctf: Real-time CTF determination and correction. J. Struct. Biol. 193, 1–12 (2016).
pubmed: 26592709
pmcid: 4711343
doi: 10.1016/j.jsb.2015.11.003
Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. Elife 7 (2018).
Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
doi: 10.1002/jcc.20084
pubmed: 15264254
Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D. Biol. Crystallogr. 66, 12–21 (2010).
doi: 10.1107/S0907444909042073
pubmed: 20057044
Takagi, J., Erickson, H. P. & Springer, T. A. C-terminal opening mimics “inside-out” activation of integrin a5b1. Nat. Struct. Biol. 8, 412–416 (2001).
pubmed: 11323715
doi: 10.1038/87569
Fujii, Y. et al. PA tag: a versatile protein tagging system using a super high affinity antibody against a dodecapeptide derived from human podoplanin. Protein Expres Purif. 95, 240–247 (2014).
doi: 10.1016/j.pep.2014.01.009