Figure 1 depicts the different steps of CMA. After translocation the substrate proteins are rapidly degraded by the lysosomal proteases. Substrate translocation requires the presence of hsc70 inside the lysosomal lumen, which may act by either pulling substrates into the lysosomes or preventing their return to the cytosol. For instance, research with artificial CMA substrate showed that hsc70 chaperone binding to substrate or lysosomal binding does not necessarily require the substrate protein to be capable of unfolding, however, lysosomal translocation makes unfolding as a necessary criteria for it to be internalized. Here, the translocation complex chooses only the substrate proteins which can unfold for internalization by the lysosomes. 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. 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. 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.
0 kommentar(er)
