Why is CD63 also called LAMP-3?

Because it is a lysosome-associated membrane protein. A GYEVM motif in its cytoplasmic tail binds the adaptor complex AP-3 and directs it to late endosomes and lysosomes, where it is most abundant.

Why does CD63 run as a smear on a Western blot?

Its large extracellular loop carries three N-linked glycans of variable composition. The added and heterogeneous sugar mass makes CD63 run as a broad band well above the size of its protein core.

Is CD63 a marker of exosomes specifically?

It marks vesicles of endosomal origin more closely than CD9 does, because it resides in late endosomes. Studies show it is not present on every vesicle and that some is also released from the plasma membrane, so it is reported as a fraction rather than a yes or no.

What does CD63 do apart from marking vesicles?

It sorts cargo into intraluminal vesicles, as shown for PMEL in pigment cells, regulates the trafficking of partner proteins such as the transporter OCT2, takes part in secretory granule maturation, and acts as a cell surface receptor for TIMP-1.

Has the structure of CD63 been solved experimentally?

Not for the full-length protein. The structure (Figure 1) is an AlphaFold computational prediction, which is useful for orientation but is not an experimental measurement.

Esta referencia está disponible actualmente en inglés. La versión en español está en preparación.

CD63 (LAMP-3): Endosomal Trafficking and Biological Roles

Revisado por el equipo editorial de ExaVeyra Sciences · Actualizado el 19 de octubre de 2026

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CD63 was the first tetraspanin to be characterized, and it is the one most closely tied to the inside of the cell.¹ A short signal in its tail sends it to late endosomes and lysosomes, which is why it is also known as lysosome-associated membrane protein 3, or LAMP-3.^2,3

That route places CD63 on the small vesicles that form inside endosomes, the same vesicles released as exosomes.¹ This page explains how CD63 travels, what it does in endosomes and storage granules, how it signals at the cell surface, and how it is detected.

Understanding the structure of CD63

CD63 is a tetraspanin of 238 amino acids with the family’s four membrane helices. Its large extracellular loop spans residues 103 to 203 and carries three asparagines that receive N-linked sugars, at positions 130, 150 and 172.³

Those sugars dominate how CD63 appears in the laboratory. The protein core is small, but its heterogeneous glycans make it run as a broad band well above its predicted size on a Western blot.⁴

No experimental structure of full-length CD63 has been published. The model shown here is a computational prediction from the AlphaFold database (see Fig. 1 below).⁵

Ribbon model of tetraspanin CD63 lying on its side, four teal transmembrane helices with the blue large extracellular loop at one end carrying three amber asparagine side chains — **Fig. 1 | Tetraspanina CD63, estructura predicha.** Hélices transmembrana (verde azulado), bucle extracelular grande (azul) y las tres asparaginas que portan sus azúcares unidos en N (barras ámbar). Modelo AlphaFold AF-P08962-F1, una predicción computacional. ²²

A lysosomal targeting motif directs CD63 to late endosomes

The cytoplasmic tail of CD63 ends in the motif glycine, tyrosine, glutamate, valine, methionine, written GYEVM. Rous and colleagues showed that this motif binds the adaptor protein complex AP-3 through a tyrosine-dependent interaction that correlates with delivery to lysosomes.²

CD63 that reaches the plasma membrane is taken back in, mainly by clathrin-dependent endocytosis. Pols and Klumperman described the result: CD63 is present at the surface in tetraspanin microdomains but is most abundant in late endosomes and lysosomes (Fig. 2).¹

The same machinery delivers CD63 to specialized storage organelles. Harrison-Lavoie and colleagues found that CD63 reaches Weibel-Palade bodies, the storage granules of endothelial cells, by an AP-3-dependent route after those granules have budded from the Golgi.⁶

Diagram of CD63 moving from the Golgi to late endosomes, cycling through the plasma membrane by endocytosis, and leaving multivesicular bodies as exosomes or toward lysosomes — **Fig. 2 | How CD63 travels.** AP-3 sends it from the Golgi to late endosomes, endocytosis returns surface CD63, and multivesicular bodies either release their intraluminal vesicles as exosomes or fuse with lysosomes.Imagen: ExaVeyra Sciences, figura originalAfter Rous et al., Mol Biol Cell 2002; Pols and Klumperman, Exp Cell Res 2009; van Niel et al., Dev Cell 2011.

CD63 sorts cargo into intraluminal vesicles

Late endosomes fill with small intraluminal vesicles as their membrane buds inward, becoming multivesicular bodies. CD63 is enriched on those internal vesicles, and when a multivesicular body fuses with the plasma membrane they are released as exosomes (Fig. 3).⁷

Transmission electron micrograph of a cell surface with small round exosomes outside the membrane and multivesicular bodies inside, 500 nm scale bar — **Fig. 3 |** Transmission electron micrograph of a cultured B cell with multivesicular bodies (MVB) inside and newly released exosomes at its surface. Scale bar 500 nm.Imagen: James R. Edgar, BMC Biology, via Wikimedia Commons, CC BY 4.0Edgar JR. Q&A: What are exosomes, exactly? BMC Biol. 2016;14:46. DOI article

Van Niel and colleagues showed that CD63 does more than ride along. In pigment cells it sorts the luminal domain of the protein PMEL into intraluminal vesicles by a route that does not use the ESCRT machinery, a step needed for the fibrils that shape melanosomes.⁸

Without CD63, the PMEL fragment was diverted toward ESCRT-dependent degradation instead. That finding established CD63 as an active sorting factor that decides between two endosomal pathways for a single cargo.⁸

CD63 regulates where partner proteins go

CD63 also acts as a trafficking regulator for proteins it binds. Schulze and colleagues found that CD63 interacts with the organic cation transporter OCT2 and, in polarized kidney epithelium, directs it to the correct basolateral membrane.⁹

Secretory granules show a related role. Omari and colleagues found that in mast cells, granule fusion with amphisomes, a hybrid of endosomes and autophagosomes, is regulated by CD63 and gives the granules their capacity to release exosomes.¹⁰

CD63 is a receptor for TIMP-1

TIMP-1 is best known as an inhibitor of matrix metalloproteinases, but it also signals independently of that activity. Egea and colleagues showed that binding of TIMP-1 to CD63 on the surface of human mesenchymal stem cells is essential for its effects on Wnt and beta-catenin signaling.¹¹

In that work the CD63 pathway acted through the microRNA let-7f and influenced proliferation and osteogenic differentiation.¹¹ Nicaise and colleagues found a parallel pathway in the nervous system, where TIMP-1 signals through a CD63 and beta 1 integrin complex to support oligodendrocyte maturation.¹²

CD63 is a marker of endosome-derived vesicles

Because it rides on intraluminal vesicles, CD63 marks the endosomal fraction of extracellular vesicles.^13,14 Mathieu and colleagues tracked CD63 and CD9 in living cells and found CD63 resident in late endosomes and released in vesicles less readily than plasma membrane CD9.¹⁵

Ai and colleagues showed that syntenin drives the vesicular secretion of CD63 by blocking its endocytosis,¹⁶ and Fordjour and colleagues found that exosome cargo proteins bud far more efficiently from the plasma membrane than from endosomes. CD63 itself was not required for that budding.¹⁷

CD63 also makes vesicle release visible. Verweij and colleagues expressed CD63 fused to a pH-sensitive fluorescent protein in zebrafish embryos and followed endogenous exosomes as they traveled through the circulation and were taken up by other cells.¹⁸

How CD63 is measured on vesicles

Four electron micrograph panels of round cup-shaped vesicles beside a Western blot with a CD63 band above the 58 kDa marker and a TSG101 band between the 36 and 58 kDa markers — **Fig. 4 | Left.** Vesicles from an ultracentrifugation pellet by electron microscopy, with their characteristic round shape. Right: a Western blot in which glycosylated CD63 runs above the 58 kDa marker, well above the size of its protein core.Imagen: Gallo A, Tandon M, Alevizos I, Illei GG, PLoS ONE, via Wikimedia Commons, CC0 1.0Gallo A, Tandon M, Alevizos I, Illei GG. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One. 2012;7(3):e30679. Fig 1.

Gallo and colleagues showed both views of one preparation: cup-shaped vesicles by electron microscopy and a glycosylated CD63 band above 58 kDa by Western blot (Fig. 4).⁴

Single-vesicle platforms show that CD63 is not on every vesicle. Breitwieser and colleagues found that CD9, CD63 and CD81 combinations distinguish vesicles from different cell types and that the tetraspanin profile of stromal cell vesicles shifts with culture conditions.¹⁹

Multiplex bead assays evaluated by Wiklander and colleagues detect dozens of surface markers at once,²⁰ and the MISEV2023 guidelines from the International Society for Extracellular Vesicles describe how marker results should be reported.²¹ The quality reference on marker panels explains why the positive fraction matters.

Where to go from here

The CD9 and CD81 references cover the two plasma membrane tetraspanins that CD63 is measured alongside, and the tetraspanin family page explains the fold all three share.

Verified practices can request lot-specific characterization data with the certificate of analysis. Our team can explain how a CD63 result was measured and what it represents.

Referencias

Numeradas en el orden en que se citan en el texto. Cada estudio indica su diseño y, cuando incluyó personas, cuántas, con una línea que dice qué respalda en esta página. Las fuentes primarias son normas, documentos de agencias y bases de datos de referencia.

1.Pols MS, Klumperman J. Trafficking and function of the tetraspanin CD63. Experimental Cell Research. 2009. doi:10.1016/j.yexcr.2008.09.020. PMID: 18930046.Narrative reviewLandmarkReference 1 supports: Foundational review of CD63 trafficking. Cited for CD63 as the first characterized tetraspanin, its clathrin-dependent endocytosis and its enrichment on intraluminal vesicles.
2.Rous BA, Reaves BJ, Ihrke G, et al. Role of adaptor complex AP-3 in targeting wild-type and mutated CD63 to lysosomes. Molecular Biology of the Cell. 2002. doi:10.1091/mbc.01-08-0409. PMID: 11907283.In vitroLandmarkReference 2 supports: Binding and localization studies of the CD63 tail. Cited for the GYEVM motif and its tyrosine-dependent interaction with AP-3.
3.NCBI Gene 967, CD63 molecule (Homo sapiens). Accessed 19 October 2026.Primary source
4.Gallo A, Tandon M, Alevizos I, et al. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One. 2012. doi:10.1371/journal.pone.0030679. PMID: 22427800.In vitroReference 4 supports: Source of the electron micrographs and CD63 Western blot (Fig. 4). Cited for the appearance of vesicles by electron microscopy and of glycosylated CD63 on a blot.
5.Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021. doi:10.1038/s41586-021-03819-2. PMID: 34265844.In vitroReference 5 supports: The AlphaFold method behind the predicted CD63 structure (Fig. 1). Cited so the model is read as a computational prediction with a stated method rather than a measurement.
6.Harrison-Lavoie KJ, Michaux G, Hewlett L, et al. P-selectin and CD63 use different mechanisms for delivery to Weibel-Palade bodies. Traffic. 2006. doi:10.1111/j.1600-0854.2006.00415.x. PMID: 16683915.In vitroLandmarkReference 6 supports: Trafficking studies in endothelial cells. Cited for CD63 reaching Weibel-Palade bodies by an AP-3-dependent route after they bud.
7.Andreu Z, Yáñez-Mó M. Tetraspanins in extracellular vesicle formation and function. Frontiers in Immunology. 2014. doi:10.3389/fimmu.2014.00442. PMID: 25278937.Narrative reviewReference 7 supports: Review of tetraspanins in vesicle biogenesis and uptake. Cited for the place of CD63 among the most abundant vesicle membrane proteins.
8.van Niel G, Charrin S, Simoes S, et al. The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Developmental Cell. 2011. doi:10.1016/j.devcel.2011.08.019. PMID: 21962903.PreclinicalReference 8 supports: Cell culture and mouse studies of PMEL sorting. Cited for CD63 directing ESCRT-independent sorting into intraluminal vesicles during melanosome biogenesis.
9.Schulze U, Brast S, Grabner A, et al. Tetraspanin CD63 controls basolateral sorting of organic cation transporter 2 in renal proximal tubules. FASEB Journal. 2017. doi:10.1096/fj.201600901R. PMID: 28031320.PreclinicalReference 9 supports: Interaction and knockout studies of CD63 with OCT2. Cited for CD63 directing a transporter to the basolateral membrane of polarized epithelium.
10.Omari S, Roded A, Eisenberg M, et al. Mast cell secretory granule fusion with amphisomes coordinates their homotypic fusion and release of exosomes. Cell Reports. 2024. doi:10.1016/j.celrep.2024.114482. PMID: 38985670.In vitroReference 10 supports: Secretory granule biogenesis in mast cells. Cited for CD63 regulating granule fusion with amphisomes and the resulting capacity to release exosomes.
11.Egea V, Zahler S, Rieth N, et al. Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling. Proceedings of the National Academy of Sciences of the United States of America. 2012. doi:10.1073/pnas.1115083109. PMID: 22223664.In vitroReference 11 supports: Knockdown and signaling studies in human mesenchymal stem cells. Cited for TIMP-1 binding to surface CD63 being essential for its effects on beta-catenin signaling and osteogenic differentiation.
12.Nicaise AM, Johnson KM, Willis CM, et al. TIMP-1 Promotes Oligodendrocyte Differentiation Through Receptor-Mediated Signaling. Molecular Neurobiology. 2019. doi:10.1007/s12035-018-1310-7. PMID: 30121936.In vitroReference 12 supports: Signaling studies in oligodendrocyte progenitors. Cited for TIMP-1 acting through a CD63 and beta 1 integrin receptor complex.
13.Kowal J, Arras G, Colombo M, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proceedings of the National Academy of Sciences of the United States of America. 2016. doi:10.1073/pnas.1521230113. PMID: 26858453.In vitroReference 13 supports: Proteomics of vesicle subtypes. Cited for the presence of exosomal and non-exosomal subpopulations within small vesicles and for CD63-based immuno-isolation.
14.Rubinstein E, Théry C, Zimmermann P. Tetraspanins affect membrane structures and the trafficking of molecular partners: what impact on extracellular vesicles? Biochemical Society Transactions. 2025. doi:10.1042/BST20240523. PMID: 40135387.Narrative reviewReference 14 supports: Review of tetraspanin roles in vesicle formation and composition. Cited for CD63 as a widely used vesicle marker whose formative role is still being defined.
15.Mathieu M, Névo N, Jouve M, et al. Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9. Nature Communications. 2021. doi:10.1038/s41467-021-24384-2. PMID: 34282141.In vitroReference 15 supports: Live tracking of CD63 and CD9. Cited for CD63 residing in late endosomes and being released in vesicles less readily than CD9.
16.Ai Y, Guo C, Garcia-Contreras M, et al. Endocytosis blocks the vesicular secretion of exosome marker proteins. Science Advances. 2024. doi:10.1126/sciadv.adi9156. PMID: 38718108.In vitroReference 16 supports: Cell biology of tetraspanin marker secretion. Cited for syntenin driving vesicular secretion of CD63 by blocking its endocytosis.
17.Fordjour FK, Guo C, Ai Y, et al. A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes. Journal of Biological Chemistry. 2022. doi:10.1016/j.jbc.2022.102394. PMID: 35988652.In vitroReference 17 supports: Cargo-based analysis of exosome protein budding. Cited for more efficient budding from the plasma membrane than from endosomes and for budding that did not require CD63.
18.Verweij FJ, Revenu C, Arras G, et al. Live Tracking of Inter-organ Communication by Endogenous Exosomes In Vivo. Developmental Cell. 2019. doi:10.1016/j.devcel.2019.01.004. PMID: 30745143.PreclinicalReference 18 supports: CD63-pHluorin imaging in zebrafish embryos. Cited for following endogenous exosomes through the circulation to their uptake by other cells.
19.Breitwieser K, Koch LF, Tertel T, et al. Detailed Characterization of Small Extracellular Vesicles from Different Cell Types Based on Tetraspanin Composition by ExoView R100 Platform. International Journal of Molecular Sciences. 2022. doi:10.3390/ijms23158544. PMID: 35955677.In vitroReference 19 supports: Single-vesicle tetraspanin profiling across cell types. Cited for cell-type-specific CD9, CD63 and CD81 combinations and for stromal cell vesicle profiles that shift with culture conditions.
20.Wiklander OPB, Bostancioglu RB, Welsh JA, et al. Systematic Methodological Evaluation of a Multiplex Bead-Based Flow Cytometry Assay for Detection of Extracellular Vesicle Surface Signatures. Frontiers in Immunology. 2018. doi:10.3389/fimmu.2018.01326. PMID: 29951064.In vitroReference 20 supports: Evaluation of a multiplex bead assay for 37 vesicle surface markers. Cited as an example of how CD63 is measured alongside other markers.
21.Welsh JA, Goberdhan DCI, O’Driscoll L, et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. Journal of Extracellular Vesicles. 2024. doi:10.1002/jev2.12404. PMID: 38326288.Clinical guidelineReference 21 supports: The current ISEV reporting guidelines. Cited for how vesicle marker results should be characterized and reported.

Fuentes de las figuras

22.AlphaFold model AF-P08962-F1, Tetraspanin CD63 (predicted). ExaVeyra Sciences, rendered in PyMOL from AlphaFold Protein Structure Database model AF-P08962-F1 (EMBL-EBI and Google DeepMind), CC BY 4.0. Publicación de la estructura: Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596(7873):583-589.

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