The other two isoforms LAMP-2B and LAMP-2C are involved in macroautophagy and vesicular trafficking, respectively. LAMP-2A a single span membrane protein, is one of the three spliced variants of a single gene lamp2. This substrate protein-chaperone complex binds to lysosome-associated membrane protein type 2A (LAMP-2A), which acts as the receptor for this pathway. This CMA-targeting motif is recognized by a cytosolic chaperone, heat shock cognate protein of 70 kDa (hsc70) which targets the substrate to the lysosome surface. In one mechanism for a protein to be a CMA substrate, it must have in its amino acid sequence a pentapeptide motif biochemically related to KFERQ. Although hsc70 targets cytosolic protein to CMA based on specific amino acid sequence recognition, it works differently when targeting proteins to macro or microautophagy. Specific selection of proteins for degradation in all forms of autophagy came to further understanding as studies discovered the role of chaperones like hsc70. Therefore, some of the components that participate in CMA are present in the cytosol while others are located at the lysosomal membrane ( Table I). The proteins that are degraded through CMA are cytosolic proteins or proteins from other compartments once they reach the cytosol. The unique features of this type of autophagy are the selectivity on the proteins that are degraded by this pathway and the direct shuttling of these proteins across the lysosomal membrane without the requirement for the formation of additional vesicles ( Figure 1). Chaperone-mediated autophagy ( CMA) refers to the chaperone-dependent selection of soluble cytosolic proteins that are then targeted to lysosomes and directly translocated across the lysosome membrane for degradation.
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