Nicolas William J, Shiriaeva Anna, Martynowycz Michael W, Grey Angus C, Ruma Yasmeen N, Donaldson Paul J, Gonen Tamir
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Howard Hughes Medical Institute, University of California, Los Angeles, CA, USA.
Nat Commun. 2025 Mar 26;16(1):2977. doi: 10.1038/s41467-025-57903-6.
Human lens fiber membrane intrinsic protein MP20 is the second most abundant membrane protein of the human eye lens. Despite decades of effort its structure and function remained elusive. Here, we determined the MicroED structure of full-length human MP20 in lipidic-cubic phase to a resolution of 3.5 Å. MP20 forms tetramers each of which contain 4 transmembrane α-helices that are packed against one another forming a helical bundle. We find that each MP20 tetramer formed adhesive interactions with an opposing tetramer in a head-to-head fashion. Investigation of MP20 localization in human lenses indicate that in young fiber cells MP20 is initially localized to the cytoplasm in differentiating fiber cells but upon fiber cell maturation is inserted into the plasma membrane, correlating with the restriction of the diffusion of extracellular tracers into the lens. Together these results suggest that MP20 forms lens thin junctions in vivo, confirming its role as a structural protein in the human eye lens essential for its optical transparency.
人晶状体纤维膜内在蛋白MP20是人眼晶状体中含量第二丰富的膜蛋白。尽管经过数十年的努力，其结构和功能仍不清楚。在此，我们在脂质立方相中确定了全长人MP20的微晶电子衍射结构，分辨率为3.5埃。MP20形成四聚体，每个四聚体包含4个跨膜α螺旋，它们相互堆积形成一个螺旋束。我们发现每个MP20四聚体以头对头的方式与相对的四聚体形成粘附相互作用。对人晶状体中MP20定位的研究表明，在年轻的纤维细胞中，MP20最初定位于分化纤维细胞的细胞质中，但在纤维细胞成熟后插入质膜，这与细胞外示踪剂向晶状体扩散的限制相关。这些结果共同表明，MP20在体内形成晶状体紧密连接，证实了其作为人眼晶状体中对其光学透明度至关重要的结构蛋白的作用。
