Structure of Collagen Receptor Integrin α1I Domain Carrying the Activating Mutation E317A

Lahti, Matti; Bligt, Eva; Niskanen, Henri; Parkash, Vimal; Brandt, Anna-Maria; Jokinen, Johanna; Patrikainen, Pekka; Käpylä, Jarmo; Heino, Jyrki; Salminen, Tiina A.

doi:10.1074/jbc.m111.261909

Cited by 20 publications

(34 citation statements)

References 58 publications

(75 reference statements)

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“…This result was surprising, because both Mg 2ϩ and Mn 2ϩ support binding of collagen IV to ␣1␤1 at these concentrations (42,58), and crystallographic data on integrin I domains support the concept that Mg 2ϩ -and Mn 2ϩ -bound I domains form essentially identical structures (65). These data, in conjunction with the recently reported crystal structure of ␣1I with the activating mutation E317A (32), led us to propose a model for collagenbinding integrin I domain activation that provides a structural basis for the enhanced activating ability of Mn 2ϩ and the inability of Ca 2ϩ to mediate ligand binding (Fig. 9).…”

Section: Discussionsupporting

confidence: 74%

“…Collagen ligand binding leads to conversion back to the more stable hexa-coordinate geometry and induces allosteric changes in the C-terminal helices. Importantly, Mg 2ϩ ions pay a significant energetic penalty for deviating from a hexacoordinate (octahedral) geometry, whereas Mn 2ϩ is capable of adopting lower coordination states (32). Thus, Mn 2ϩ , with a lower energetic barrier to adopting the activated conformation, is more effective at driving the opening of the ␣C helix and enabling ligand binding.…”

Section: Discussionmentioning

confidence: 99%

“…Although computational models have been proposed for the ␣1I open conformation (27) and for the ␣1I/collagen interaction site (31), no structures of ␣1I in complex with any type of ligand or ligandmimetic peptide have been reported (2). Recently, the structure of ␣1I containing an activating mutation (E317A) was determined (32). This protein adopted a novel conformation that differed from both the open and closed structures previously published for other integrins, indicating that the activation mechanism of collagen-binding integrins may differ from that of other integrins.…”

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confidence: 99%

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Dynamic Structural Changes Are Observed upon Collagen and Metal Ion Binding to the Integrin α1 I Domain

Weinreb

Gao

et al. 2012

Journal of Biological Chemistry

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Background: Integrin ␣1 I domain undergoes conformational changes upon collagen binding. Results: Deuterium exchange was used to measure the effects of cations, collagen, or an antibody on the ␣1I solution structure. Conclusion: Full-length collagen and metal ions induce changes that differ in key aspects from previously proposed models for ␣1I activation. Significance: These studies support a new model for integrin I domain activation.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Dynamic Structural Changes Are Observed upon Collagen and Metal Ion Binding to the Integrin α1 I Domain

Weinreb

Gao

et al. 2012

Journal of Biological Chemistry

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“…8 is consistent with a significant shift difference between helix ␣7 and associated global structural changes toward open conformation (12). It is surprising, therefore, that this helix was unperturbed in a recent crystal structure of the ␣1 I domain containing a double C139S/E317A substitution (32). This inconsistency may be due to the different experimental conditions used in the NMR and crystallization experiments and the fact that the crystal lattice may impose a constraint that favors a conformation that is likely to be only one of multiple interconverting conformations present under solution.…”

Section: Discussionmentioning

confidence: 60%

“…On the other hand, mutation of the Thr 221 in the ␣2 I domain results in loss of adhesion to collagen I in the isolated ␣2 I domain as well as when it is expressed in the full-length integrin ␣2 subunit (34). Finally, the E317A substitution in the ␣1 I domain results in a domain with increased binding to both collagens I and IV, an effect that is maintained when the same mutation is expressed in the whole integrin ␣1 subunit in cells (32). Thus, it is clear that not all mutations that alter the binding of the ␣1 I domain to its natural ligand result in the same changes in the context of the whole integrin.…”

Section: Discussionmentioning

confidence: 89%

Enhancing Integrin α1 Inserted (I) Domain Affinity to Ligand Potentiates Integrin α1β1-mediated Down-regulation of Collagen Synthesis

Shi

Pedchenko

Greer

et al. 2012

Journal of Biological Chemistry

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Background: Integrin ␣1␤1 binding to collagen IV down-regulates collagen synthesis, but how modulating integrin ␣1␤1 affinity alters collagen homeostasis is unknown. Results: Cells carrying mutations of the ␣1 subunit with enhanced collagen binding show increased ERK activation and increased collagen down-regulation. Conclusion: Enhancing the affinity of the ␣1 subunit to collagen potentiates integrin ␣1␤1-mediated outside-in signaling. Significance: These findings have major implications for pathological conditions such as fibrotic diseases.

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Intrinsic local destabilization of the C‐terminus predisposes integrin α1 I domain to a conformational switch induced by collagen binding

et al. 2016

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Integrin-collagen interactions play a critical role in a myriad of cellular functions that include immune response, and cell development and differentiation, yet their mechanism of binding is poorly understood. There is increasing evidence that conformational flexibility assumes a central role in the molecular mechanisms of protein-protein interactions and here we employ NMR hydrogen-deuterium exchange (HDX) experiments to explore the impact of slower timescale dynamic events. To gain insight into the mechanisms underlying collagen-induced conformational switches, we have undertaken a comparative study between the wild type integrin a1 I and a gain-of-function E317A mutant. NMR HDX results suggest a relationship between regions exhibiting a reduced local stability in the unbound I domain and those that undergo significant conformational changes upon binding. Specifically, the aC and a7 helices within the C-terminus are at the center of such major perturbations and present reduced local stabilities in the unbound state relative to other structural elements. Complementary isothermal titration calorimetry experiments have been performed to derive complete thermodynamic binding profiles for association of the collagen-like triple-helical peptide with wild type a1 I and E317A mutant. The differential energetics observed for E317A are consistent with the HDX experiments and support a model in which intrinsically destabilized regions predispose Abbreviations: a1 I, alpha1 I domain; NMR, nuclear magnetic resonance; HDX, hydrogen-deuterium exchange; HSCQ, heteronuclear single-quantum correlation; MIDAS, metal ion-dependent adhesion site; THP, collagen-like triple helical peptide; ITC, isothermal titration calorimetry; CD, circular dichroism.Additional Supporting Information may be found in the online version of this article.Integrin-collagen interactions play a critical role in cell adhesion processes. To gain insight into the mechanisms underlying collageninduced conformational switches, we have undertaken a comparative NMR study between the human integrin a1 I and a gain-offunction E317A mutant. Our results, supported by thermodynamic measurements, suggest that intrinsically destabilized regions facilitate conformational rearrangements of integrin I domain. This study highlights the importance of exploring slow dynamics to delineate allosteric and binding events. Published by Wiley-Blackwell. V C 2016 The Protein Society conformational rearrangement in the integrin I domain. This study highlights the importance of exploring different timescales to delineate allosteric and binding events.

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Structure of Collagen Receptor Integrin α1I Domain Carrying the Activating Mutation E317A

Cited by 20 publications

References 58 publications

Dynamic Structural Changes Are Observed upon Collagen and Metal Ion Binding to the Integrin α1 I Domain

Dynamic Structural Changes Are Observed upon Collagen and Metal Ion Binding to the Integrin α1 I Domain

Enhancing Integrin α1 Inserted (I) Domain Affinity to Ligand Potentiates Integrin α1β1-mediated Down-regulation of Collagen Synthesis

Intrinsic local destabilization of the C‐terminus predisposes integrin α1 I domain to a conformational switch induced by collagen binding

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