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The proteins that are degraded through CMA are cytosolic proteins or proteins from other compartments once they reach the cytosol. Therefore, some of the components that participate in CMA are present in the cytosol while others are located at the lysosomal membrane (Table I).

Selectivity of proteins for degradation is a primary role for chaperone, hsc70 in CMA and also in selective forms of microautophagy and macroautophagy. For instance. in macroautophagy, hsc70 binds to hydrophobic amino acids in the undesired protein which in a process known as "chaperone-assisted selective autophagy (CASA)." However, the role of hsc70, here, is distinct from the way it targets proteins to CMA. Selectivity in the process of autophagy came to have known in discovering the role of hsc70.

Specific selection of proteins for degradation in all forms of autophagy came to further understanding as studies discovered the role of chaperones like hsc70. Although hsc70 targets cytosolic protein to CMA based on specific amino acid sequence recognition, it works differently when targeting proteins to macro or microatuophagy.

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. 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. This substrate protein-chaperone complex binds to lysosome-associated membrane protein type 2A (LAMP-2A), which acts as the receptor for this pathway. LAMP-2A a single span membrane protein, is one of the three spliced variants of a single gene lamp2. The other two isoforms LAMP-2B and LAMP-2C are involved in macroautophagy and vesicular trafficking, respectively. Substrate proteins undergo unfolding after binding to LAMP-2A in a process likely mediated by the membrane associated hsc70 and its co-chaperones Bag1, hip, hop and hsp40, also detected at the lysosomal membrane. This binding of substrates to monomers of LAMP-2A triggers the assembly of LAMP-2A multimers that act as the active translocation complex through which the substrates can pass through after unfolding. The translocation complex here requires the protein substrate to have the capability to unfold in order to enter lysosomes. Research with artificial CMA substrate showed that hsc70 chaperone binding to substrate or lysosomal binding does not necessarily require susbtrate protein to be capable of unfolding, however, lysosomal translocation makes unfolding as a necessary criteria for it to internalize the lysosomes.


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