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The melanosome: membrane dynamics in black and white

Nature Reviews Molecular Cell Biology volume 2, pages 738–748 (2001)Cite this article

Abstract

Melanosomes are morphologically and functionally unique organelles within which melanin pigments are synthesized and stored. Melanosomes share some characteristics with lysosomes, but can be distinguished from them in many ways. The biogenesis and intracellular movement of melanosomes and related organelles are disrupted in several genetic disorders in mice and humans. The recent characterization of genes defective in these diseases has reinvigorated interest in the melanosome as a model system for understanding the molecular mechanisms that underlie intracellular membrane dynamics.

Key Points

  • Melanosomes are specialized organelles within melanocytes and retinal pigment epithelial cells, where melanins, the major pigments made by mammals, are synthesized and stored. Melanosomes are one of several "lysosome-related" organelles singularly expressed in various tissues; these diverse organelles display unique morphological and functional characteristics but also share features with conventional lysosomes.

  • Lysosome-related organelles, including melanosomes, are functionally disrupted in a group of genetic disorders in humans and mice, including Hermansky-Pudlak, Chediak-Higashi, and Griscelli syndromes. These disorders are due to defects in protein transport, morphogenesis, or intracellular movement of lysosome-related organelles. Melanosomes serve as the best current model system in which to define the molecular basis of the disease-associated defects.

  • Among the gene products deficient in Hermansky-Pudlak syndrome and related disorders are several involved in vesicular transport — including the adaptor complex AP-3, the SNARE-associated protein palladin, and the α-subunit of rab geranylgeranyltransferase. Testable models for how these and other less-characterized disease-associated proteins function in melanosome biogenesis are being developed and are based on recent advances in our understanding of the endosomal origins of melanosome precursors, the role of multivesicular bodies, and the segregation of melanosomes from lysosomes. Morphological and biochemical analyses of melanosome resident proteins in melanocytes from affected mice and individuals are beginning to refine these models.

  • Griscelli's syndrome and related disorders in humans and mice result from defects in the intracellular movement and distribution of melanosomes and other lysosome-related organelles. Associated gene products regulate capture of melanosomes in the periphery of melanocytes, which are required for subsequent transfer of melanin to keratinocytes. Study of these gene products and the effects of their loss have provided new paradigms for the roles of a rab protein (Rab27a), a rab effector protein (melanophilin), and an unconventional myosin (myosin Va) in mediating actin-dependent organelle movement.

  • Further study of melanosome biology in normal and diseased cells is likely to provide us with new paradigms to explain how conserved mechanisms are manipulated to effect the generation of structurally and functionally unique organelles and how intracellular organelle movement and positioning is regulated.

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Figure 1: Melanosome maturation.
Figure 2: Post-Golgi sorting in conventional cell types and melanocytes.
Figure 3: Model of protein/lipid transport between organelles.
Figure 4: Model of melanosome transport in epidermal melanocytes.
Figure 5: Molecular mechanisms of melanosome transport.

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Acknowledgements

The authors would like to thank D.C. Bennett, J.S. Bonifacino, C.G. Burd, D.F. Cutler, E.C. Dell'Angelica, L.B. King, and members of the Marks and Seabra labs for their contributions and critical comments on the manuscript. We are grateful to Graça Raposo for critical contributions to many of the models described here. Particular thanks go to L. Collinson and C. Hopkin for the electron micrograph in figure 1. We gratefully acknowledge support by grant R01 EY 12207 from the National Eye Institute of the National Institutes of Health to M.S.M and grants from the Wellcome Trust, the Medical Research Council, and Foundation Fighting Blindness to M.C.S.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104-6082, PA, USA

    Michael S. Marks

  2. Division of Biomedical Sciences, Faculty of Medicine, Imperial College, London, SW7 2AZ, UK

    Miguel C. Seabra

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  1. Michael S. Marks
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Related links

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DATABASE LINKS

Locuslink:

AIM-1

AP-3

ashen

dsu

gunmetal

HPS1

HPS3

myosin Va

myosin VI

myosin VIIa

OA1

pallidin

Pmel17

Rab3a

Rab27a

Rab38

Rab geranylgeranyl transferase

 OMIM:

Chediak Higashi syndrome

Griscelli syndrome

Hermansky–Pudlak syndrome

OCA2

Usher syndrome type 1B

 SGD:

Sec2

Sec4

 Swiss-Prot:

CHS1

TRP1

Glossary

LYSOSOMAL HYDROLASES

Soluble enzymes found in lysosomes that are involved in the hydrolytic breakdown of macromolecules. They include proteases, lipases and glycosidases.

RETINAL PIGMENT EPITHELIAL CELLS

These pigmented cells form an epithelial layer underneath photoreceptors and function in the degradation of photoreceptor outer segments.

CHOROIDAL MELANOCYTES

Pigmented melanocytes within the choroid of the eye, adjacent to the pigment epithelia. These cells probably function as an additional barrier to prevent light scattering inside the eye.

VACUOLAR SYSTEM

The series of interconnected membrane-enclosed organelles of the secretory and endocytic pathways.

COATS

Coat proteins, such as clathrin, COPI and COPII, are thought to link cargo recruitment to vesicle formation within the vacuolar system.

SNARES

SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins are a family of membrane-tethered coiled–coil proteins that regulate fusion reactions and target specificity in the vacuolar system.

RABS

Rab proteins form the largest subfamily of small GTPases of the Ras superfamily. They regulate budding, tethering, fusion and motility at various sites within cells.

MULTIVESICULAR BODIES

Endosomal intermediates in which small membrane vesicles are enclosed within a limiting membrane. The internal vesicles are thought to form by invagination and budding from the limiting membrane.

CLATHRIN

One type of coat protein that, when polymerized, forms a characteristic electron-dense structure on its target membrane. Clathrin binds to membranes through adaptor complexes, such as AP-1 and AP-2.

AP-3

A heterotetrameric adaptor complex similar in structure to the clathrin-associated adaptors AP-1 and AP-2. It is not yet clear whether AP-3 physiologically interacts with clathrin.

DENSE GRANULES AND α GRANULES

Two types of secretory granules within platelets and megakaryocytes, the release of which is required for proper blood clotting. α granules contain fibrinogen, von Willebrand factor and other clotting factors. Dense granules contain serotonin, calcium, pyrophosphate and nucleotides. Dense granules are compromised or absent in platelets of patients and mouse models with Hermansky–Pudlak syndrome.

WEIBEL–PALADE BODIES

Morphologically unique secretory structures of endothelial cells, within which von Willebrand factor is stored for eventual release.

PDZ DOMAIN

An approximately 90-residue structural motif found in many cytosolic proteins. PDZ domains regulate protein–protein interactions, largely by binding to a specific tripeptide motif.

MANNOSE 6-PHOSPHATE RECEPTORS

These receptors transport soluble lysosomal hydrolases to late endosomes by cycling between the TGN and late endosomes. They bind in the TGN to mannose 6-phosphate moieties on N-linked glycans of the hydrolases. They release the hydrolases in late endosomes and return to the TGN for another round of transport.

DYNEIN/DYNACTIN

Dynein is a motor protein complex involved in minus-end-directed microtubule transport. Dynactin is a biochemically separable complex that links dynein to target organelles.

IQ MOTIF

A small structural domain that mediates interactions with calmodulin.

LYTIC GRANULES

Lysosome-like secretory organelles of cytotoxic T lymphocytes and natural killer cells. They contain pore-forming proteins, toxins and proteases that facilitate killing of target cells.

IMMUNOLOGICAL SYNAPSE

A tight junction between T lymphocytes and target cells. For cytotoxic T cells, it is a site for secretion of lytic granule contents.

GDP/GTP EXCHANGE FACTOR

All members of the Ras superfamily of GTPases cycle between an active GTP- and an inactive GDP-bound state. Following GTP hydrolysis (usually facilitated by a GTPase-activating protein or GAP), exchange factors (GEFs) facilitate release of the GDP and binding of the more abundant GTP. GEFs are therefore required for activation of Rab proteins.

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Marks, M., Seabra, M. The melanosome: membrane dynamics in black and white. Nat Rev Mol Cell Biol 2, 738–748 (2001). https://doi.org/10.1038/35096009

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