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

Abstract

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.

Unique transmembrane domain interactions differentially modulate integrin αvβ3 and αIIbβ3 function

“…Although the αIIb and αv TM domains each contain a small residue-x 3 -small residue motif in approximately the same position, their van der Waal surfaces are certainly distinct and distinguishable, since computationally designed TM domain peptides were able to interact exclusively with either αv or αIIb (30). Then, it is not surprising that β3 can interact with αv and αIIb via distinct interfaces, varying in affinity (17,31).…”

Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

“…From the PMF, the association free energy was estimated similar to reference [67], following the approach for a two-body membrane system by Johnston et al [43] In short, the PMF is integrated along the reaction coordinate for dimeric states only. From this, an association constant (K a ; eq.…”

“…S1A and S1B), which is a prerequisite for applying WHAM to extract a PMF from these distributions. [66,67] The RMSD to the respective starting structures during each umbrella sampling simulation reached a stable plateau after 40 ns in the individual windows (similar to the RMSD determined in the unbiased simulations; Fig. S2), and the average RMSD of the backbone atoms indicates overall moderate structural changes in the individual umbrella sampling windows with RMSD ≈ 3.7 Å for the whole protein and~2.4 Å only considering the transmembrane helices for both dimeric configurations (Tables S1 and S2).…”

“…Other studies computing PMFs of membrane systems also report relaxation times of 30-50 ns, which is in line with our results. [67,81,82] For all simulations, the integrity of the membrane structure and the position of the dimers therein was evaluated in terms of the spatial distribution of the electron density of the membrane components, with systems for both interfaces showing highly similar and evenly distributed electron densities (Fig. S3).…”

Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration

“…The performed unbiased microsecond-long MD simulations at the atomistic level in explicit solvent and an explicit lipid bilayer are currently the most accurate way to computationally explore structure and dynamics of transmembrane proteins (49). We used established parameterizations for the solvent (31), lipids (50), and proteins (51), which we had also applied successfully in other transmembrane protein simulations (52,53). We performed quintuplicate MD simulations for each system, which allows probing for the influence of the starting conditions and helps overcoming the sampling challenge (54).…”