Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
J Biol Chem. 2023 Apr;299(4):104574. doi: 10.1016/j.jbc.2023.104574. Epub 2023 Mar 3.
Caveolin-1 (CAV1) is a membrane-sculpting protein that oligomerizes to generate flask-shaped invaginations of the plasma membrane known as caveolae. Mutations in CAV1 have been linked to multiple diseases in humans. Such mutations often interfere with oligomerization and the intracellular trafficking processes required for successful caveolae assembly, but the molecular mechanisms underlying these defects have not been structurally explained. Here, we investigate how a disease-associated mutation in one of the most highly conserved residues in CAV1, P132L, affects CAV1 structure and oligomerization. We show that P132 is positioned at a major site of protomer-protomer interactions within the CAV1 complex, providing a structural explanation for why the mutant protein fails to homo-oligomerize correctly. Using a combination of computational, structural, biochemical, and cell biological approaches, we find that despite its homo-oligomerization defects P132L is capable of forming mixed hetero-oligomeric complexes with WT CAV1 and that these complexes can be incorporated into caveolae. These findings provide insights into the fundamental mechanisms that control the formation of homo- and hetero-oligomers of caveolins that are essential for caveolae biogenesis, as well as how these processes are disrupted in human disease.
窖蛋白-1（CAV1）是一种膜重塑蛋白，它通过寡聚化生成被称为小窝的质膜凹陷的烧瓶状凹陷。CAV1 中的突变与人类的多种疾病有关。这些突变通常干扰寡聚化和细胞内运输过程，这些过程是成功组装小窝所必需的，但这些缺陷的分子机制尚未得到结构解释。在这里，我们研究了 CAV1 中高度保守残基之一 P132L 的一种疾病相关突变如何影响 CAV1 的结构和寡聚化。我们表明，P132 位于 CAV1 复合物中单体-单体相互作用的主要部位，为为什么突变蛋白不能正确地同源寡聚化提供了结构解释。我们使用计算、结构、生化和细胞生物学方法的组合，发现尽管 P132L 存在同源寡聚化缺陷，但它能够与 WT CAV1 形成混合异源寡聚复合物，并且这些复合物可以被纳入小窝。这些发现为控制窖蛋白同源和异源寡聚体形成的基本机制提供了深入了解，这些机制对于小窝的生物发生至关重要，以及这些过程如何在人类疾病中被破坏。
