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Identification of human immunodeficiency virus type 1 (HIV-1) gp120-binding sites on scavenger receptor cysteine rich 1 (SRCR1) domain of gp340.

ABSTRACT: BACKGROUND: gp340, a member of scavenger receptor cysteine rich family encoded by Deleted in Malignant Brain Tumors 1 (DMBT1), is an important component in innate immune defense. The first scavenger receptor cysteine rich domain (SRCR1) of gp340 has been shown to inhibit HIV-1 infection through binding to the N-terminal flank of the V3 loop of HIV-1 gp120. RESULTS: Through homology modeling and docking analysis of SRCR1 to a gp120-CD4-X5 antibody complex, we identified three loop regions containing polar or acidic residues that directly interacted with gp120. To confirm the docking prediction, a series of over-lapping peptides covering the SRCR1 sequence were synthesized and analyzed by gp120-peptide binding assay. Five peptides coincide with three loop regions showed the relative high binding index. An alanine substitution scan revealed that Asp34, Asp35, Asn96 and Glu101 in two peptides with the highest binding index are the critical residues in SRCR1 interaction with gp120. CONCLUSION: We pinpointed the vital gp120-binding regions in SRCR1 and narrowed down the amino acids which play critical roles in contacting with gp120.

SUBMITTER: Chu Y

PROVIDER: S-EPMC3721995 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Identification of human immunodeficiency virus type 1 (HIV-1) gp120-binding sites on scavenger receptor cysteine rich 1 (SRCR1) domain of gp340.

Chu Ying Y Li Jiahuang J Wu Xilin X Hua Zichun Z Wu Zhiwei Z

Journal of biomedical science 20130701

<h4>Background</h4>gp340, a member of scavenger receptor cysteine rich family encoded by Deleted in Malignant Brain Tumors 1 (DMBT1), is an important component in innate immune defense. The first scavenger receptor cysteine rich domain (SRCR1) of gp340 has been shown to inhibit HIV-1 infection through binding to the N-terminal flank of the V3 loop of HIV-1 gp120.<h4>Results</h4>Through homology modeling and docking analysis of SRCR1 to a gp120-CD4-X5 antibody complex, we identified three loop re ...[more]

PMID: 23815775

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Project description:BackgroundInsufficient clearance of soluble oligomeric amyloid-? peptide (oA?) in the central nervous system leads to the synaptic and memory deficits in Alzheimer's disease (AD). Previously we have identified scavenger receptor class A (SR-A) of microglia mediates oligomeric amyloid-? peptide (oA?) internalization by siRNA approach. SR-A is a member of cysteine-rich domain (SRCR) superfamily which contains proteins actively modulating the innate immunity and host defense, however the functions of the SRCR domain remain unclear. Whether the SRCR domain of SR-AI modulates the receptor surface targeting and ligand internalization was investigated by expressing truncated SR-A variants in COS-7 cells. Surface targeting of SR-A variants was examined by live immunostaining and surface biotinylation assays. Transfected COS-7 cells were incubated with fluorescent oA? and acetylated LDL (AcLDL) to assess their ligand-internalization capabilities.ResultGenetic ablation of SR-A attenuated the internalization of oA? and AcLDL by microglia. Half of oA?-containing endocytic vesicles was SR-A positive in both microglia and macrophages. Clathrin and dynamin in SR-AI-mediated oA? internalization were involved. The SRCR domain of SR-AI is encoded by exons 10 and 11. SR-A variants with truncated exon 11 were intracellularly retained, whereas SR-A variants with further truncations into exon 10 were surface-targeted. The fusion of exon 11 to the surface-targeted SR-A variant lacking the SRCR domain resulted in the intracellular retention and the co-immunoprecipitation of Bip chaperon of the endoplasmic reticulum. Surface-targeted variants were N-glycosylated, whereas intracellularly-retained variants retained in high-mannose states. In addition to the collagenous domain, the SRCR domain is a functional binding domain for oA? and AcLDL. Our data suggest that inefficient folding of SR-AI variants with truncated SRCR domain was recognized by the endoplasmic reticulum associated degradation which leads to the immature N- glycosylation and intracellular retention.ConclusionThe novel functions of the SRCR domain on regulating the efficacy of receptor trafficking and ligand binding may lead to possible approaches on modulating the innate immunity in Alzheimer's disease and atherosclerosis.

Dataset Information

Identification of human immunodeficiency virus type 1 (HIV-1) gp120-binding sites on scavenger receptor cysteine rich 1 (SRCR1) domain of gp340.

Publications

Identification of human immunodeficiency virus type 1 (HIV-1) gp120-binding sites on scavenger receptor cysteine rich 1 (SRCR1) domain of gp340.

Similar Datasets

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