Chaperone mediated autophagy mechanism

Chaperone mediated autophagy mechanism. The scheme shows the principal events in CMA mediated translocation of proteins through the lysosomal membrane and known regulatory mechanisms. (A) LAMP-2A exist as an inactive oligomer at the lysosomal membrane. CMA protein substrates containing KFERQ motifs and HSC70 can bind to the cytosolic tail of LAMP-2A with similar affinity. The short C-terminal tail of LAMP-2A exposed to the cytoplasm and conformed by 12 amino acids probably binds to the chaperone and the substrate in a competitive manner. However, on the substrate, binding sites for HSC70 and LAMP-2A do not overlap allowing the HSC70-substrate complexes to interact with LAMP-2A oligomer in a substrate dependent manner. (B) In a dynamic fashion, GFAP favors the formation of high molecular weight aggregates of LAMP2A. Somehow, coupled and simultaneous binding of the substrate to HSC70 and LAMP-2A is sensed by the transmembrane domains of the LAMP-2A for rearrangements in the supramolecular complexes. Next, substrate unfolding and translocation to the lysosomal lumen occurs. A lysosomal-HSC70 (Lys-hsc70) collaborates in this process. (C) A signaling pathway involving phosphorylating and dephosphorylating signals, where AKT, MTORC2, PHLPP1, RAC1, and GFAP, regulate the stabilization of the LAMP-2A complex at lysosomal membranes.

Publication

Chaperone Mediated Autophagy in the Crosstalk of Neurodegenerative Diseases and Metabolic Disorders. (2018) Iván E. Alfaro, et al. Front Endocrinol (Lausanne). 2018;9:778. Figure: F1. All organisms Homo sapiens Danio rerio

Disease mentions