<br>溶酶体相关膜蛋白 2a 型 (LAMP-2A) 跨膜结构域的结构揭示了伴侣介导的自噬中底物特异性的关键特征。,Journal of Biological Chemistry

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溶酶体相关膜蛋白 2a 型 (LAMP-2A) 跨膜结构域的结构揭示了伴侣介导的自噬中底物特异性的关键特征。
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2014 Dec 19 , DOI: 10.1074/jbc.m114.609446
Ashok K Rout ₁ , Marie-Paule Strub ₁ , Grzegorz Piszczek ₂ , Nico Tjandra ₃

Affiliation

分子伴侣介导的自噬 (CMA) 是一种高度调控的细胞过程，介导溶酶体中选择性细胞质蛋白子集的降解。增加 CMA 活性是细胞应对应激的一种方式，它会导致非关键胞浆蛋白转化为能量来源的增加，或从胞浆中清除不需要或受损的蛋白质。溶酶体相关膜蛋白 2a 型 (LAMP-2A) 以及分子伴侣和共分子伴侣复合物是 CMA 的关键调节因子。 LAMP-2A 是一种跨膜蛋白成分，用于将蛋白质易位至溶酶体。在这里，我们通过核磁共振（NMR）研究了正十二烷基磷酸胆碱胶束中人 LAMP-2A 跨膜结构域的结构和动力学。我们发现LAMP-2A以同源三聚体的形式存在，其中跨膜螺旋相互缠绕形成平行的卷曲螺旋构象，而其胞质尾部是柔性的并暴露于胞质溶胶。 LAMP-2A 的胞质尾部与分子伴侣 Hsc70 和 CMA 底物 RNase A 相互作用，具有相当的亲和力，但不与 Hsp40 和 RNase S 肽相互作用。由于底物和分子伴侣复合物可以同时结合，从而产生双峰相互作用，因此我们提出分子伴侣的底物识别和LAMP-2A对溶酶体膜的靶向是耦合的。这可以增加底物亲和力和特异性，并防止底物聚集，协助底物解折叠，并促进易位所需的 LAMP-2A 高级复合物的形成。

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Structure of transmembrane domain of lysosome-associated membrane protein type 2a (LAMP-2A) reveals key features for substrate specificity in chaperone-mediated autophagy.

Chaperone-mediated autophagy (CMA) is a highly regulated cellular process that mediates the degradation of a selective subset of cytosolic proteins in lysosomes. Increasing CMA activity is one way for a cell to respond to stress, and it leads to enhanced turnover of non-critical cytosolic proteins into sources of energy or clearance of unwanted or damaged proteins from the cytosol. The lysosome-associated membrane protein type 2a (LAMP-2A) together with a complex of chaperones and co-chaperones are key regulators of CMA. LAMP-2A is a transmembrane protein component for protein translocation to the lysosome. Here we present a study of the structure and dynamics of the transmembrane domain of human LAMP-2A in n-dodecylphosphocholine micelles by nuclear magnetic resonance (NMR). We showed that LAMP-2A exists as a homotrimer in which the membrane-spanning helices wrap around each other to form a parallel coiled coil conformation, whereas its cytosolic tail is flexible and exposed to the cytosol. This cytosolic tail of LAMP-2A interacts with chaperone Hsc70 and a CMA substrate RNase A with comparable affinity but not with Hsp40 and RNase S peptide. Because the substrates and the chaperone complex can bind at the same time, thus creating a bimodal interaction, we propose that substrate recognition by chaperones and targeting to the lysosomal membrane by LAMP-2A are coupled. This can increase substrate affinity and specificity as well as prevent substrate aggregation, assist in the unfolding of the substrate, and promote the formation of the higher order complex of LAMP-2A required for translocation.

更新日期：2017-01-31

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