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9.A.16 The Lysosomal Protein Import (LPI) Family

Lysosomes take up and degrade proteins by several endocytic pathways. Additionally, they take up cytosolic proteins for degradation in a process termed chaperone-mediated autophagy. Substrate proteins contain a targeting sequence related to KFERQ. Hsc70 and cochaperones stimulate, at least in part, by unfolding the substrate prior to transport. Chaperones in the lysosomal lumen are also required for uniport. The receptor at the cytoplasmic surface is 'lysosome-associated membrane protein 2a' (lamp2a) (Cuervo and Dice 2000). Levels of lamp2a are regulated proportionally to the activity of the pathway. Although the translocon has not been identified, lamp2a may form the channel. It multimerizes into tetramers, octamers and higher oligomers and might insert into the membrane. The native preprotein is predicted to have 2 TMSs, one at the N-terminus and one at the C-terminus. The energy source is not known, but ATP-dependent chaperones have been implicated in the process. Other constituents are not known. LAMP1 and 2 stabilize TAPL (ABCB9; TC# 3.A.1.209.2) (Majeski and Dice 2004). May play a role in Parkinson disease (Gan-Or et al. 2015).

In addition, binding of the cardiac hormone, atrial natriuretic peptide (ANP), to transmembrane guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), also called LAMP1 (9.A.16.1.1) produces the intracellular second messenger cGMP in target cells. A conserved FQQI motif in the protein is essential for the internalization and subcellular trafficking of NPRA during hormone signaling in intact murine mesagial cells (Mani et al. 2016).

The overall transport reaction catalyzed by the lamp2a complex is:

Unfolded protein (cytoplasm) → Unfolded protein (lysosomal lumen)

 

 

References associated with 9.A.16 family:

Agarraberes, F.A. and J.F. Dice (2001). Protein translocation across membranes. Biochim. Biophys. Acta 1513: 1-24. 11427190
Cuervo, A.M. and J.F. Dice. (2000). Regulation of lamp2a levels in the lysosomal membrane. Traffic 1: 570-583. 11208145
Demirel O., Jan I., Wolters D., Blanz J., Saftig P., Tampe R. and Abele R. (2012). The lysosomal polypeptide transporter TAPL is stabilized by interaction with LAMP-1 and LAMP-2. J Cell Sci. 125(Pt 18):4230-40. 22641697
Gan-Or, Z., P.A. Dion, and G.A. Rouleau. (2015). Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 11: 1443-1457. 26207393
Gao J., Xia L., Lu M., Zhang B., Chen Y., Xu R. and Wang L. (2012). TM7SF1 (GPR137B): a novel lysosome integral membrane protein. Mol Biol Rep. 39(9):8883-9. 22729905
Majeski, A.E. and J.F. Dice. (2004). Mechanisms of chaperone-mediated autophagy. Int J Biochem. Cell Biol. 36: 2435-2444. 15325583
Mani, I., R. Garg, and K.N. Pandey. (2016). Role of FQQI motif in the internalization, trafficking, and signaling of guanylyl-cyclase/natriuretic peptide receptor-A in cultured murine mesangial cells. Am. J. Physiol. Renal Physiol 310: F68-84. 26377794