Pashkova Natalya, Peterson Tabitha A, Ptak Christopher P, Winistorfer Stanley C, Guerrero-Given Debbie, Kamasawa Naomi, Ahern Christopher A, Shy Michael E, Piper Robert C
Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Carver College of Medicine NMR Facility, University of Iowa, Iowa City, IA 52242, USA.
iScience. 2024 Sep 19;27(11):110989. doi: 10.1016/j.isci.2024.110989. eCollection 2024 Nov 15.
Peripheral Myelin Protein 22 (PMP22) and MPZ are abundant myelin membrane proteins in Schwann cells. The MPZ adhesion protein holds myelin wraps together across the intraperiod line. PMP22 is a tetraspan protein belonging to the Claudin superfamily. Loss of either MPZ or PMP22 causes severe demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy, and duplication of PMP22 causes the most common form of CMT, CMT1A. Yet, the molecular functions provided by PMP22 and how its alteration causes CMT are unknown. Here, we find MPZ and PMP22 form a specific complex through interfaces within their transmembrane domains. We also find that the PMP22 A67T patient variant that causes a loss-of-function (hereditary neuropathy with pressure palsies) phenotype maps to this interface, and blocks MPZ association without affecting localization to the plasma membrane or interactions with other proteins. These data define the molecular basis for the MPZ ∼ PMP22 interaction and indicate this complex fulfills an important function in myelinating cells.
外周髓鞘蛋白22（PMP22）和髓鞘蛋白零（MPZ）是施万细胞中丰富的髓鞘膜蛋白。MPZ黏附蛋白将髓鞘包裹物跨周期间线维系在一起。PMP22是一种属于紧密连接蛋白超家族的四次跨膜蛋白。MPZ或PMP22的缺失都会导致严重的脱髓鞘性夏科-马里-图思（CMT）周围神经病，而PMP22的重复会导致最常见形式的CMT，即CMT1A。然而，PMP22所提供的分子功能以及其改变如何导致CMT尚不清楚。在此，我们发现MPZ和PMP22通过其跨膜结构域内的界面形成一种特定复合物。我们还发现导致功能丧失（遗传性压力性麻痹）表型的PMP22 A67T患者变体定位于此界面，并阻断MPZ缔合，而不影响其在质膜上的定位或与其他蛋白的相互作用。这些数据确定了MPZ与PMP22相互作用的分子基础，并表明这种复合物在髓鞘形成细胞中发挥重要功能。
