Transmembrane-domain-driven heterodimer assembly licenses integrin head-domain folding in the endoplasmic reticulum

Three TMD-disruptive mutations in the integrin β1-subunit activate function but reduce surface expression, with the β1-LR (Leu748Arg) mutation causing embryonic lethality in mice.

• Why it matters: It was unclear whether integrin transmembrane domain (TMD) interactions do more than regulate activation, especially during ER biogenesis and folding.
• What they did: In mice, cell biology and biochemistry showed that β1 TMD–TMD interactions drive efficient β-heterodimer assembly, enabling coupled folding of the ER-luminal βI-domain.
• The result: Disrupting TMD interactions caused ER retention and luminal domain-dependent ER-associated degradation of monomeric misfolded β1, and analogous human β TMD–disrupting mutations impair cell surface expression and cause severe loss-of-function disease.