LAMP1

Official Full Name

lysosomal associated membrane protein 1

Organism

Homo sapiens

GeneID

3916

Background

The protein encoded by this gene is a member of a family of membrane glycoproteins. This glycoprotein provides selectins with carbohydrate ligands. It may also play a role in tumor cell metastasis. [provided by RefSeq, Jul 2008]

Synonyms

LAMPA; CD107a; LGP120;

Bio Chemical Class

Lysosomal protein import

Protein Sequence

MAAPGSARRPLLLLLLLLLLGLMHCASAAMFMVKNGNGTACIMANFSAAFSVNYDTKSGPKNMTFDLPSDATVVLNRSSCGKENTSDPSLVIAFGRGHTLTLNFTRNATRYSVQLMSFVYNLSDTHLFPNASSKEIKTVESITDIRADIDKKYRCVSGTQVHMNNVTVTLHDATIQAYLSNSSFSRGETRCEQDRPSPTTAPPAPPSPSPSPVPKSPSVDKYNVSGTNGTCLLASMGLQLNLTYERKDNTTVTRLLNINPNKTSASGSCGAHLVTLELHSEGTTVLLFQFGMNASSSRFFLQGIQLNTILPDARDPAFKAANGSLRALQATVGNSYKCNAEEHVRVTKAFSVNIFKVWVQAFKVEGGQFGSVEECLLDENSMLIPIAVGGALAGLVLIVLIAYLVGRKRSHAGYQTI

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Detailed Information

Recent Progress

Lysosome-associated membrane protein (LAMP) 1/CD107a is used as a marker for NK-cell degranulation. Secretory lysosomes of natural killer (NK) cells, containing perforin and granzymes, are indispensable for NK-cell cytotoxicity. It was shown that LAMP1 silencing caused inhibition of NK-cell cytotoxicity, and LAMP1 RNA interference (RNAi) cells failed to deliver granzyme B to target cells. Reduction of LAMP1 expression affected the movement of lytic granules and resulted in decreased levels of perforin, but not granzyme B, in the granules. In LAMP1 RNAi cells, more perforin was retained outside of lysosomal compartments in trans-Golgi network-derived transport vesicles. Disruption of expression of LAMP1 binding partner, adaptor protein 1 (AP-1) sorting complex, also caused retention of perforin in the transport vesicles and inhibited cytotoxicity, indicating that the interaction between AP-1 sorting complex and LAMP1 on the surface of the transport vesicles is important for perforin trafficking to lytic granules. Thus it was concluded that the decreased level of perforin in lytic granules of LAMP1-deficient cells, combined with disturbed motility of the lytic granules, can lead to the inability to deliver apoptosis-inducing granzyme B to target cells and to inhibition of NK-cell cytotoxicity.

Lassa virus is a zoonotic, hemorrhagic fever-causing pathogen. Because the virus can spread as an aerosol and there has been no approved vaccines or specific antiviral drugs currently available, it poses a major impact on human health, affecting annually up to half a million people in West-African countries. Entry of the virus into the cells is the first step where the virus could be stopped. LAMP-1 is one of the proteins to interact with Lassa virus. In order to determine the molecular mechanism of this process, researchers used high-resolution electron cryomicroscopy and tomography techniques to image chemically-inactivated Lassa virus. Analysis of non-infectious virus-like particles at different pH and in the presence of human LAMP-1, revealed specific structural rearrangements in the surface protein spike, providing a molecular-level rationale for this important stage of host cell entry(Fig.1).

Fig. 1. The conserved histidine triad is important for LAMP1 binding. (Li et al, 2016)

Duchenne muscular dystrophy is a disease that results from loss of the protein dystrophin, which links the intracellular cytoskeletal network with the extracellular matrix, but deficiency in this function does not fully explain the onset or progression of the disease. To analyze the secretome profile of myotubes, researchers labeled the proteins of mdx and wild-type myotubes with stable isotope-labeled amino acids (SILAC), including LAMP1, which co-localized in vesicles with an over-secreted cytoskeletal protein, MLC1 (myosin light chain 1). These LAMP1/MLC1-3-positive vesicles accumulated in the cytosol of myotubes and were secreted into the culture medium in a range of abnormal densities. These results suggested that a lack of dystrophin may lead to a general dysregulation of vesicle trafficking. It was proposed that disturbance of the export of proteins through vesicles occurs before the myonecrotic cascade and contributes chronically to the pathophysiology of DMD, thereby presenting a range of new potential therapeutic targets.

Expression of LAMP1 on the surface correlates with metastatic potential of B16 melanoma cells. Downregulation of their expression in high metastatic (B16F10) cells reduced their surface expression and metastatic potential. In order to explore if overexpression of LAMP1 on the surface of low metastatic (B16F1) cells can augment their metastatic ability, B16F1 cells were transduced with lentiviral vector carrying mutant-LAMP1 (Y386A) (mutLAMP1). Results revealed that pre-incubation with anti-LAMP1 antibodies significantly reduced lung metastasis of B16F10 cells. Overexpression of mutLAMP1 significantly increased its surface expression on B16F1 cells, leading to increased cellular spreading and motility on fibronectin and matrigel. LAMP1 is the major carrier of poly-N-acetyllactosamine (polyLacNAc) on B16F10 cells. However, significantly higher expression of mutLAMP1 had no effect on galectin-3 binding on cell surface or on spreading or motility of cells on galectin-3-coated plates. These findings, taken together, suggested that PolyLacNAc and galectin-3 are the major participants in melanoma metastasis. Although surface LAMP1 promotes interactions with organ ECM and BM, carbohydrates on LAMP1 play a decisive role in dictating lung metastasis.

References:

Cohen-Dvashi, H., Cohen, N., Israeli, H., & Diskin, R. (2015). Molecular mechanism for lamp1 recognition by lassa virus. Journal of Virology, 89(15), 7584.
Krzewski, K., Gil-Krzewska, A., Nguyen, V., Peruzzi, G., & Coligan, J. E. (2013). Lamp1/cd107a is required for efficient perforin delivery to lytic granules and nk-cell cytotoxicity. Blood, 121(23), 4672-4683.
Li, S., Sun, Z., Pryce, R., Parsy, M. L., Fehling, S. K., & Schlie, K., et al. (2016). Acidic ph-induced conformations and lamp1 binding of the lassa virus glycoprotein spike. Plos Pathogens, 12(2), e1005418.
Duguez, S., Duddy, W., Johnston, H., Lainé, J., Le, B. M., & Brown, K. J., et al. (2013). Dystrophin deficiency leads to disturbance of lamp1-vesicle-associated protein secretion. Cellular & Molecular Life Sciences, 70(12), 2159-2174.
Jiang, D. B., Sun, L. J., Cheng, L. F., Zhang, J. P., Xiao, S. B., & Sun, Y. J., et al. (2017). Recombinant dna vaccine of hantavirus gn and lamp1 induced long-term immune protection in mice. Antiviral Research, 138, 32-39.
Agarwal, A. K., Srinivasan, N., Godbole, R., More, S. K., Budnar, S., & Gude, R. P., et al. (2015). Role of tumor cell surface lysosome-associated membrane protein-1 (lamp1) and its associated carbohydrates in lung metastasis. Journal of Cancer Research & Clinical Oncology, 141(9), 1563-1574.

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