SORL1
Description
The SORL1 (sortilin related receptor 1) is a protein-coding gene located on chromosome 11.
Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene. SORL1 (also known as SORLA, SORLA1, or LR11; SORLA or SORL1 are used, often interchangeably, for the protein product of the SORL1 gene) is a 2214 residue type I transmembrane protein receptor that binds certain peptides and integral membrane protein cargo in the endolysosomal pathway and delivers them for sorting to the retromer multi protein complex; the gene is predominantly expressed in the central nervous system. Endosomal traffic jams linked to SORL1 retromer dysfunction are the earliest cellular pathology in both familial and the more common sporadic Alzheimer’s patients. Retromer regulates protein trafficking from the early endosome either back to the trans-Golgi (retrograde) or back to the plasma membrane (direct recycling). Two forms of retromer are known: the VPS26A retromer and the VPS26B retromer, the latter being dedicated to direct recycling in the CNS. SORL1 is a multi domain single-pass membrane protein whose large ectodomain resides primarily in endosomal tubules, being connected by its transmembrane helical domain and cytoplasmic tail to the VPS26 retromer subunit on the outer endosomal membrane. The age at onset of SORL1 mutation carriers varies, which has complicated segregation analyses. Nevertheless, protein−truncating variants (PTVs) are observed almost exclusively in AD patients, indicating that SORL1 is haploinsufficient. However, most variants are rare missense variants that can be benign, or risk−increasing, but recent reports have indicated that some variants are causative for disease. In fact, specific missense variants have been observed only in AD cases, some of which may have a dominant negative effect..[1] [2] ALZFORUM has created an interactive web page that maps all of the currently known variants onto the schematic of the SORLA domain structure shown in the Figure on the right, along with information for each one. It can be accessed at https://www.alzforum.org/mutations/sorl1
== Clinical significance == A significant reduction in SORL1 (LR11) expression has been found in brain tissue of Alzheimer's disease patients.
SORL1 is a sorting receptor that plays a crucial role in directing various proteins to their correct locations within the cell. It works with the AP-1 complex to sort proteins between the Golgi apparatus and endosomes. SORL1 is particularly important in regulating the intracellular trafficking and processing of amyloid precursor protein (APP), preventing the formation of amyloid-beta peptides, and potentially directing newly produced amyloid-beta peptides to lysosomes for degradation. SORL1 also acts as a sorting receptor for BDNF receptor NTRK2/TRKB, facilitating its trafficking between synaptic plasma membranes, postsynaptic densities, and the cell soma, thereby positively regulating BDNF signaling. It promotes GDNF regulated secretion and is involved in a GDNF clearance pathway by sorting the GDNF-GFRA1 complex to endosomes and directing GDNF to lysosomes for degradation. SORL1 also regulates ERBB2/HER2 subcellular distribution, promoting its recycling from endosomes to the plasma membrane and stimulating PI3K-dependent ERBB2 signaling. In addition, SORL1 promotes the localization of lipoprotein lipase (LPL) to endosomes and lysosomes, leading to degradation of newly synthesized LPL. It is also a potential sorting receptor for APOA5, facilitating its internalization and directing a portion for degradation in lysosomes and another portion for sorting to the trans-Golgi network. SORL1 promotes the recycling of internalized insulin receptor (INSR) via the Golgi apparatus back to the cell surface, preventing its lysosomal catabolism and increasing INSR cell surface expression, which strengthens insulin signal reception in adipose tissue. It is involved in renal ion homeostasis by controlling the phospho-regulation of SLC12A1/NKCC2 through intracellular sorting of STK39 and PPP3CB. SORL1 stimulates the proliferation and migration of smooth muscle cells by increasing cell surface expression of the urokinase receptor uPAR/PLAUR, potentially accelerating intimal thickening following vascular injury. It promotes monocyte adhesion and stimulates proliferation and migration of monocytes/macrophages, contributing to intimal thickening and macrophage foam cell formation in atherosclerosis. It regulates hypoxia-enhanced adhesion of hematopoietic stem and progenitor cells to bone marrow stromal cells through a PLAUR-mediated pathway. SORL1 is a metabolic regulator that maintains the balance between lipid storage and oxidation in response to changing environmental conditions. It may regulate signaling by the heterodimeric neurotrophic cytokine CLCF1-CRLF1 bound to the CNTFR receptor by promoting the endocytosis of the complex and lysosomal degradation. SORL1 may also regulate IL6 signaling by decreasing cis signaling and up-regulating trans signaling. It interacts with various proteins, including APP, BACE1, LRPAP1, GGA1, GGA2, PACS1, neurotensin, PDGFB, uPA receptor PLAUR, uPA, PAI1, tPA, AP-1, AP-2, BMPR1A, BMPR1B, LPL, GDNF, GDNF receptor alpha-1, GFRA2, GFRA3, GFRA4, INSR, STK39, CRLF1, CLC, CNTFR, IL6, IL6R, APOE, APOA5, ROCK2, PPP3CB, NTRK2/TRKB, and HSPA12A. These interactions are involved in various cellular processes, including protein trafficking, signaling, and lipid metabolism.
SORL1 is also known as C11orf32, LR11, LRP9, SORLA, SorLA-1, gp250.
