Annular Anionic Lipids Stabilize the Integrin αIIbβ3 Transmembrane Complex

Schmidt, Thomas; Suk, Jae-Eun; Ye, Feng; Situ, Alan J.; Mazumder, Parichita; Ginsberg, Mark H.; Ulmer, Tobias S.

doi:10.1074/jbc.m114.623504

Cited by 22 publications

(29 citation statements)

References 58 publications

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“…First, we performed unbiased microsecond-long MD simulations at the atomistic level in explicit solvent and an explicit lipid bilayer on the three TMDs, likely the currently most accurate way to explore structure and dynamics of transmembrane proteins 73 . The length of our MD simulations surpasses comparable previous ones on integrin TMDs by at least one order of magnitude 51 , 74 , 75 . We performed triplicate MD simulations for each system, which allows probing for the influence of the starting conditions and determining the significance of the computed results by statistical testing and rigorous error estimation 46 .…”

Section: Discussionmentioning

confidence: 41%

“…In agreement with ref. 51 , the R995-D723 salt bridge dissociates intermittently, as indicated by occupancies ≪100%. However, the MD simulations reveal that, among all four possible salt bridges that can form in the membrane-proximal region, R995-D723 is the most prevalent interaction, followed by R995-E726, and R997-E726 is the least prevalent one.…”

Section: Resultsmentioning

confidence: 99%

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On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation

Pagani

Gohlke

2018

Sci Rep

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Integrins are α/β heterodimeric transmembrane adhesion receptors. Evidence exists that their transmembrane domain (TMD) separates upon activation. Subunit-specific differences in activation sensitivity of integrins were reported. However, whether sequence variations in the TMD lead to differential TMD association has remained elusive. Here, we show by molecular dynamics simulations and association free energy calculations on TMDs of integrin αIIbβ3, αvβ3, and α5β1 that αIIbβ3 TMD is most stably associated; this difference is related to interaction differences across the TMDs. The order of TMD association stability is paralleled by the basal activity of these integrins, which suggests that TMD differences can have a decisive effect on integrin conformational free energies. We also identified a specific order of clasp disintegration upon TMD dissociation, which suggests that the closed state of integrins may comprise several microstates. Our results provide unprecedented insights into a possibly contributing role of TMD towards subunit-specific sensitivity of integrin activation.

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Section: Discussionmentioning

confidence: 41%

Section: Resultsmentioning

confidence: 99%

On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation

Pagani

Gohlke

2018

Sci Rep

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“…Based mostly on studies of the αIIbβ3 integrin it has been widely assumed that the TM/CT of β integrins have an intrinsic affinity for the corresponding domains of their cognate α subunits, such that they will form constitutively inactive heterodimers. Many studies have shown the isolated αIIb and β3 TM associate to form heterodimers in model membranes or as fusion proteins in E. coli or model cell lines (Lau et al, 2009; Berger et al, 2010; Partridge et al, 2005; Zhu et al, 2010; Schneider and Engelman, 2004; Schmidt et al, 2015; Lokappa et al, 2014; Kim et al, 2009). We observed similar results for heterodimerization of the α5 and β1 TM/CT, an observation consistent with evidence that this particular β1 integrin is activated according to the canonical model (Takagi et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Implications of the differing roles of the β1 and β3 transmembrane and cytoplasmic domains for integrin function

Mathew

Jiang

et al. 2016

eLife

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Integrins are transmembrane receptors composed of α and β subunits. Although most integrins contain β1, canonical activation mechanisms are based on studies of the platelet integrin, αIIbβ3. Its inactive conformation is characterized by the association of the αIIb transmembrane and cytosolic domain (TM/CT) with a tilted β3 TM/CT that leads to activation when disrupted. We show significant structural differences between β1 and β3 TM/CT in bicelles. Moreover, the ‘snorkeling’ lysine at the TM/CT interface of β subunits, previously proposed to regulate αIIbβ3 activation by ion pairing with nearby lipids, plays opposite roles in β1 and β3 integrin function and in neither case is responsible for TM tilt. A range of affinities from almost no interaction to the relatively high avidity that characterizes αIIbβ3 is seen between various α subunits and β1 TM/CTs. The αIIbβ3-based canonical model for the roles of the TM/CT in integrin activation and function clearly does not extend to all mammalian integrins.DOI: http://dx.doi.org/10.7554/eLife.18633.001

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“… a Measurements performed in 43 mM DHPC, 17 mM POPC, 25 mM NaH 2 PO 4 /Na 2 HPO 4 pH 7.4 solution at 28 °C (effective bicelle q-factor of 0.5). b ΔΔG°,′ = (ΔG° αIIb β3,mutant −ΔG° αIIb β3 ) − (ΔG° αIIb β3(A711P),mutant −ΔG° αIIb β3(A711P) ) c Measured previously by competitive binding experiments 32 , resulting in larger experimental uncertainties than direct measurements. …”

Section: Figurementioning

confidence: 99%

“… c Measured previously by competitive binding experiments 32 , resulting in larger experimental uncertainties than direct measurements. …”

Section: Figurementioning

confidence: 99%

Structural and thermodynamic basis of proline-induced transmembrane complex stabilization

Schmidt

Situ

Ulmer

2016

Sci Rep

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In membrane proteins, proline-mediated helix kinks are indispensable for the tight packing of transmembrane (TM) helices. However, kinks invariably affect numerous interhelical interactions, questioning the acceptance of proline substitutions and evolutionary origin of kinks. Here, we present the structural and thermodynamic basis of proline-induced integrin αIIbβ3 TM complex stabilization to understand the introduction of proline kinks in membrane proteins. In phospholipid bicelles, the A711P substitution in the center of the β3 TM helix changes the direction of adjacent helix segments to form a 35 ± 2° angle and predominantly repacks the segment in the inner membrane leaflet due to a swivel movement. This swivel repacks hydrophobic and electrostatic interhelical contacts within intracellular lipids, resulting in an overall TM complex stabilization of −0.82 ± 0.01 kcal/mol. Thus, proline substitutions can directly stabilize membrane proteins and such substitutions are proposed to follow the structural template of integrin αIIbβ3(A711P).

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Annular Anionic Lipids Stabilize the Integrin αIIbβ3 Transmembrane Complex

Cited by 22 publications

References 58 publications

On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation

On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation

Implications of the differing roles of the β1 and β3 transmembrane and cytoplasmic domains for integrin function

Structural and thermodynamic basis of proline-induced transmembrane complex stabilization

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