Neuronal localization of a novel mosaic apolipoprotein E receptor, LR11, in rat and human brain

Madsen

Journal of Biological Chemistry

et al. 2001

159

190

We previously isolated and sequenced the ϳ250-kDa type 1 receptor sorLA/LR11, a mosaic protein with elements characterizing the Vps10p domain receptor family as well as the low density lipoprotein receptor family. The N terminus of the Vps10p domain comprises a consensus sequence for cleavage by furin ( 50 RRKR 53 ) that precedes a truncation found in sorLA isolated from human brain. Here we show that sorLA, like sortilin-1/ neurotensin receptor-3, whose lumenal domain consists of a Vps10p domain only, is synthesized as a proreceptor that is cleaved by furin in late Golgi compartments. We show that the truncation conditions the Vps10p domain for propeptide inhibitable binding of neuropeptides and the receptor-associated protein. We further demonstrate that avid binding of the receptor-associated protein, apolipoprotein E, and lipoprotein lipase not inhibited by propeptide occurs to sites located in other lumenal domains. In transfected cells, about 10% of fulllength sorLA were expressed on the cell surface capable of mediating endocytosis. However, the major pool of receptors was found in late Golgi compartments, suggesting possible interaction with newly synthesized ligands. The results show that sorLA, following activation by truncation, binds multiple ligands and may mediate both endocytosis and sorting.

supporting

confidence: 73%

Activation and Functional Characterization of the Mosaic Receptor SorLA/LR11

Madsen

Journal of Biological Chemistry

et al. 2001

159

190

Journal of Biological Chemistry

“…As CR(1-4) and CR (1)(2)(3)(4)(5)(6)(7)(8) showed similar binding to APP-d6A as CR(1-11), our hypothesis is that CR(1-4) binds to d6A in a way that dominates over the binding sites in CR(5-8) when they are present in the longer CR(1-8) and CR(1-11) constructs. Studies are ongoing to elucidate whether the overall conformation restricts access to CR(5-8), i.e.…”

Section: Sorla Minimentioning

confidence: 69%

“…SorLA (also known as SORL1 and LR11) is an ϳ250-kDa type-1 membrane protein that is highly expressed in the neurons of both the developing and the adult central nervous system (7,8). Neuropathological studies have identified reduced SorLA expression in vulnerable neurons in the brains of AD patients (9 -13).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

See 1 more Smart Citation

SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

Mehmedbasic

Christensen

Nilsson

et al. 2015

Background: SorLA binds APP and decreases the production of A␤; however, the molecular mechanisms controlling these processes are poorly understood. Results: We identified CR(5-8) as an APP-binding site in SorLA. Conclusion: The CR-cluster is essential for the SorLA-dependent decrease in APP proteolysis. Significance: Details regarding the function of SorLA in APP metabolism might lead to an understanding of the genetic association of SorLA with Alzheimer disease.

Proc. Natl. Acad. Sci. U.S.A.

“…endocytic receptors ͉ knockout mouse ͉ neurodegeneration ͉ Vps10p-domain receptors S orting protein-related receptor (sorLA), also known as LR11, is a 250-kDa type-1 membrane protein of unknown function that is expressed in neurons of the central and peripheral nervous system (1)(2)(3)(4). The protein is a member of a family of neuronal receptors that share structural similarity with the vacuolar protein sorting 10 protein (Vps10p), a sorting protein in yeast that transports carboxypeptidase Y from the Golgi to the vacuole (5).…”

mentioning

confidence: 99%

Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein

Andersen

Reiche

Schmidt

et al. 2005

593

696

sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid ␤-peptide (A␤), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to A␤, whereas ablation of sorLA expression in knockout mice results in increased levels of A␤ in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into A␤ and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase A␤ production and plaque formation and promote spontaneous AD.endocytic receptors ͉ knockout mouse ͉ neurodegeneration ͉ Vps10p-domain receptors S orting protein-related receptor (sorLA), also known as LR11, is a 250-kDa type-1 membrane protein of unknown function that is expressed in neurons of the central and peripheral nervous system (1-4). The protein is a member of a family of neuronal receptors that share structural similarity with the vacuolar protein sorting 10 protein (Vps10p), a sorting protein in yeast that transports carboxypeptidase Y from the Golgi to the vacuole (5). Other family members include the proneurotrophin receptor sortilin (6) and the head activator-binding protein in hydra (7). Because sorLA interacts with the family of GGA (Golgi-localizing, ␥-adaptin ear homology domain, ARFinteracting) adaptors that shuttle between the Golgi and endosomes͞lysosomes, the receptor was proposed to act in intracellular protein trafficking (8). The relevance of such sorLAmediated protein transport in neurons is unclear at present. However, expression profiling has demonstrated reduction of sorLA expression in the brain of patients suffering from Alzheimer's disease (AD), suggesting a causal role for the receptor in the pathogenesis of this disease (9).Central to the pathogenesis of AD is the proteolytic processing of a neuronal membrane protein called the amyloid precursor protein (APP). APP follows a complex intracellular trafficking pathway that influences processing to either a soluble fragment sAPP␣ (nonamyloidogenic) or to sAPP␤ and the insoluble amyloid ␤-peptide (A␤), the principal component of senile plaques (10). The rate of A␤ production is considered the major risk factor for onset of AD (10). En route through the secretory pathway to the cell surface, most newly synthesized APP molecules are cleaved into sAPP␣ by ␣-secretase;...