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)
Lysosomal-associated membrane glycoprotein-1 precursor, LAMP-1 (stabilizes TAPL (TC# 3.A.1.209.2) (Demirel et al., 2012).
LAMP1 of Homo sapiens (P11279)
Lysosomal-associated membrane protein 2 precursor, LAMP2a. LAMP2 colocalizes with TM7SF1 (GRP137B) (TC#9.B.123.1.1) (Gao et al., 2012).
LAMP2a of Homo sapiens (410 aas; 2 TMSs) (P13473)
Lysosome-associated membrane glycoprotein 1-like protein of 318 aas and 2 TMSs, N- and C-terminal.
LAMP1 of Hyalella azteca
Uncharacterized protein of 306 aas and 2 TMSs, N- and C-terminal.
UP of Trachymyrmex cornetzi
Lysosome-associated membrane glycoprotein 5, LAMP, of 281 aas and 2 TMSs, N- and C-terminal.
LAMP5 of Protobothrops mucrosquamatus
Macrosialin of 418 aas and 2 TMSs.
Macrosialin of Balaenoptera acutorostrata scammoni
Uncharacterized protein of 242 aas and 2 TMSs, N- and C-terminal
UP of Oryzias melastigma