N-Linked Oligosaccharides on the Low Density Lipoprotein Receptor Homolog SorLA/LR11 Are Modified with Terminal GalNAc-4-SO4 in Kidney and Brain

Abstract

Sorting protein-related receptor (SorLA/LR11) is a highly conserved mosaic receptor that is expressed by cells in a number of different tissues including principal cells of the collecting ducts in the kidney and neurons in the central and peripheral nervous systems. SorLA/LR11 has features that indicate it serves as a sorting receptor shuttling between the plasma membrane, endosomes, and the Golgi. We have found that a fraction of SorLA/LR11 that is synthesized in the kidney and the brain bears N-linked oligosaccharides that are modified with terminal ␤1,4-linked GalNAc-4-SO 4 . Oligosaccharides located in the vacuolar sorting (Vps) 10p domain (Vps10p domain) are modified with ␤1,4-linked GalNAc when the Vps10p domain is expressed in cells along with either of two recently cloned protein-specific ␤1,4GalNAc-transferases, GalNAcTIII and GalNAcTIV. Either of two sequences with basic amino acids located within the Vps10p domain is able to mediate recognition by these ␤1,4GalNAc-transferases. The highly specific modification of oligosaccharides in the Vps10p domain of SorLA/LR11 with terminal GalNAc-4-SO 4 suggests that this unusual modification may modulate the interaction of SorLA/LR11 with proteins and influence their trafficking.Sorting protein-related receptor (SorLA), 2 also known as LR11, is a highly conserved mosaic, type 1 receptor. The luminal/extracellular domain consists of a short NH 2 -terminal sequence preceding a consensus site for furin cleavage, a vacuolar sorting (Vps) 10p domain, 5 F/YWTD/␤-propeller modules, an epidermal growth factor precursor sequence, 11 low density lipoprotein receptor (LDLR) class A (LDLR-A) repeats, and 6 fibronectin type III repeats (1, 2). The single transmembrane domain is followed by a 54-amino acid cytosolic domain containing a motif that mediates interaction with GGA (Golgilocalized, ␥-ear containing, ARF binding) proteins involved in Golgi-endosome sorting (3). The presence of these varied domains places SorLA/LR11 in a number of different families and underscores its ability to interact with a range of different ligands. A Vps10p domain is also present in the receptors sortilin-1 (4) and SorCS (5). The Vps10p domain of SorLA/ LR11 mediates the endogenous binding of the propeptide released from the N terminus of SorLA/LR11 by furin cleavage. The peptides neurotensin and hydra head activator also bind to the Vps10p domain (6). The YWTD repeats, epidermal growth factor repeat, and the LDLR class A repeats are characteristic of LDLR family members (7) and likely mediate apolipoprotein E and receptor-associated protein binding by SorLA/LR11 (6). In addition, the 6 fibronectin type III repeats are characteristic of a number of neural adhesion molecules (2).The peptide portion of SorLA/LR11 consists of 2215 amino acids with a calculated molecular weight of 247,000. The receptor migrates with M r of over 300,000 when examined by SDS-PAGE indicating that a large fraction of the 20 potential Asn-glycosylation sites present on the luminal domain are utilized. We have determin...

Retromer Regulates Postendocytic Sorting of β‐Secretase in Polarized Madin–Darby Canine Kidney Cells

“…A possible mediator could be a transmembrane receptor of the Vps10-domain family, such as sortilin (21,59,60), sortilin-related receptor (SorLA) (16,61,62) or SorCS1 (63), which have been implicated in endosome-to-Golgi retrieval of receptors through retromer. SorLA is actually expressed in kidney (64). Indeed, SorLA could be immunoprecipitated from MDCK cells, and we confirmed that Vps35 can interact with SorLA independently of APP or BACE overexpression (our unpublished data).…”

B4GALNT3 Expression Predicts a Favorable Prognosis and Suppresses Cell Migration and Invasion via β1 Integrin Signaling in Neuroblastoma

“…14 SorLA/LR11, highly expressed by neurons in the central and peripheral nervous systems, bears N-linked oligosaccharides modified with terminal ␤1,4 -linked GalNAc-4-SO 4 that can be synthesized by B4GALNT3 in CHO cells. 14 In Drosophila, ␤1,4-N-acetylgalactosaminyltransferase A (B4GALNTA) catalyzes synthesis of LacdiNAc on glycoconjugates. 15 Drosophila mutants deficient in B4GALNTA have defects in behavior and in the neuromuscular system.…”

Ablation of GalNAc-4-sulfotransferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice

“…There are a number of glycoproteins synthesized in other tissues that are also selectively modified with terminal GalNAc-4-SO 4 , for example, the LDL-receptor homolog SorLA/LR11 expressed in the kidney and the brain (48) and tenascin-R expressed in the brain (49). It is possible that additional differences between WT and GalNAc-4-ST1 -/-mice will be identified upon further examination; however, none of the other glycoproteins identified thus far as bearing structures terminating with SO 4 -4-GalNAcβ1,4GlcNAc would be expected to have an impact on steroid hormone production or reproduction.…”