Cell‐specific abnormal prenylation of Rab proteins in platelets and melanocytes of the gunmetal mouse

Zhang, Qing; Zhen, Lijie; Li, Wei; Novak, Edward K.; Collinson, Lucy M.; Jang, Elliott K.; Haslam, Richard J.; Elliott, Rosemary W.; Swank, Richard T.

doi:10.1046/j.1365-2141.2002.03444.x

Cited by 27 publications

(34 citation statements)

References 46 publications

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“…Although the reduction in RGGT activity was observed in all tissues, defects in Rab prenylation are tissue-specific (32, 34, and our unpublished observations). One possible explanation for the tissue-specific phenotype is that concentrations of Rab proteins are considerably higher in platelets and melanocytes compared with other tissues (34). Alternatively, a subset of Rabs present lower affinity for the prenylation machinery and are selectively affected whenever the enzyme is limiting (32).…”

Section: Rggtmentioning

confidence: 99%

Thematic review series: Lipid Posttranslational Modifications. Geranylgeranylation of Rab GTPases

Leung

Baron

Seabra

2006

Journal of Lipid Research

217

198

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Rab GTPases require special machinery for protein prenylation, which include Rab escort protein (REP) and Rab geranylgeranyl transferase (RGGT). The current model of Rab geranylgeranylation proposes that REP binds Rab and presents it to RGGT. After geranylgeranylation of Rab C-terminal cysteines, REP delivers the prenylated protein to membranes. The REP-like protein Rab GDP dissociation inhibitor (RabGDI) then recycles the prenylated Rab between the membrane and the cytosol. The recent solution of crystal structures of the Rab prenylation machinery has helped to refine this model and provided further insights. The hydrophobic prenyl binding pocket of RGGT and geranylgeranyl transferase type-I (GGT-I) differs from that of farnesyl transferase (FT). A bulky tryptophan residue in FT restricts the size of the pocket, whereas in RGGT and GGT-I, this position is occupied by smaller residues. A highly conserved phenylalanine in REP, which is absent in RabGDI, is critical for the formation of the REP:RGGT complex. Finally, a geranylgeranyl binding site conserved in REP and RabGDI has been identified within helical domain II. The postprenylation events, including the specific targeting of Rabs to target membranes and the requirement for single versus double geranylgeranylation by different Rabs, remain obscure and should be the subject of future studies.-Leung, K. F., R. Baron, and M. C. Seabra.

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Section: Rggtmentioning

confidence: 99%

Thematic review series: Lipid Posttranslational Modifications. Geranylgeranylation of Rab GTPases

Leung

Baron

Seabra

2006

Journal of Lipid Research

217

198

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“…BLOC-3 Interacts with Rab9-Because several Rab GTPases are involved in melanosome and platelet dense body biogenesis (27,28,29,30,31,32,33,34), we tested for interactions of various Rab proteins (i.e. Rab7, Rab9a, Rab29, Rab32, and Rab38) with HPS4 and HPS1 using the Y2H system (data not shown).…”

Section: Assembly Of Bloc-3 Depends On Multiple Sites Of Interaction mentioning

confidence: 99%

“…For instance, the gunmetal mouse lacks a functional Rab geranylgeranyl transferase (RGGT), which leads to underprenylation of Rab27a and other Rab proteins (27,31). Rab27a in turn mediates attachment of melanosomes to myosin Va through its interaction with the adaptor melanophilin, thereby enabling transport to the cell periphery along microtubules (32)(33)(34).…”

Section: Subunit Composition and Hydrodynamic Properties Of Bloc-3-rementioning

confidence: 99%

Assembly of the Biogenesis of Lysosome-related Organelles Complex-3 (BLOC-3) and Its Interaction with Rab9

Kloer¹,

Rojas

Ivan

et al. 2010

Journal of Biological Chemistry

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The Hermansky-Pudlak syndrome (HPS) is a genetic hypopigmentation and bleeding disorder caused by defective biogenesis of lysosome-related organelles (LROs) such as melanosomes and platelet dense bodies. HPS arises from mutations in any of 8 genes in humans and 16 genes in mice. Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer. Analytical ultracentrifugation reveals that this complex has a molecular mass of 146 kDa, equivalent to that of the native complex and to the sum of the predicted molecular masses of HPS1 and HPS4. This indicates that HPS1 and HPS4 interact directly in the absence of any other protein as part of BLOC-3. Limited proteolysis and deletion analyses show that both subunits interact with one another throughout most of their lengths with the sole exception of a long, unstructured loop in the central part of HPS4. An interaction screen reveals a specific and strong interaction of BLOC-3 with the GTP-bound form of the endosomal GTPase, Rab9. This interaction is mediated by HPS4 and the switch I and II regions of Rab9. These characteristics indicate that BLOC-3 might function as a Rab9 effector in the biogenesis of LROs.

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“…14,15 However, the restricted phenotype of gm/gm mice indicates that selected cell types are overly susceptible to reduced RGGT levels; even though enzyme activity is equally diminished in all gm/gm tissues tested, the degree to which specific Rabs are affected varies by cell type. 12,15,16 16 These lineage-restricted effects could result either from a high concentration of Rab proteins in target cells, so that reduced enzyme activity is limiting, or from the particular sensitivity of cell type-specific Rabs to reduced RGGT levels. Regardless of the precise mechanism, the gunmetal phenotype implies that efficient thrombopoiesis and granule biosynthesis rely on the degree of prenylation and membrane association of some Rab proteins.…”

Section: Introductionmentioning

confidence: 99%

A role for Rab27b in NF-E2-dependent pathways of platelet formation

Tiwari

Italiano

Barral

et al. 2003

Blood

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Megakaryocytes release platelets by reorganizing the cytoplasm into proplatelet extensions. Fundamental to this process is the need to coordinate transport of products and organelles in the appropriate abundance to nascent platelets. The importance of the Rab family of small GTPases (guanosine 5-triphosphatases) in platelet biogenesis is revealed in gunmetal (gm/gm) mice, which show deficient Rab isoprenylation and macrothrombocytopenia with few granules and abnormal megakaryocyte morphology. Although some Rab proteins are implicated in vesicle and organelle transport along microtubules or actin, the role of any Rab protein in platelet biogenesis is unknown. The limited number of Rab proteins with defective membrane association in gm/gm megakaryocytes prominently includes Rab27a and Rab27b. Normal expression of Rab27b is especially increased with terminal megakaryocyte differentiation and dependent on nuclear factor-erythroid 2 (NF-E2), a transcription factor required for thrombopoiesis. Chromatin immunoprecipitation demonstrates recruitment of NF-E2 to the putative Rab27B promoter. Inhibition of endogenous IntroductionMammalian blood platelets are released from bone marrow megakaryocytes (MKs) in a process that transforms the entire MK cytoplasm into long pseudopodia known as proplatelets. 1-3 Nascent platelets are assembled within these structures. 4 The need for dramatic cytoplasmic and cytoskeletal reorganization and concomitant assembly of anucleate platelets presents unusual challenges to differentiated MKs. The cellular and molecular response to these challenges is poorly understood.Selected mouse models of thrombocytopenia and qualitative platelet defects have proved invaluable in probing the molecular basis of platelet biogenesis. Mice lacking either of 2 erythromegakaryocytic transcription factors, GATA1, and nuclear factorerythroid 2 (NF-E2), show dramatically arrested MK maturation 5,6 and thus implicate their target genes in aspects of platelet assembly. However, the transcriptional targets of GATA1 and NF-E2 that are immediately relevant to MK fragmentation and platelet release are not known. Other insights derive from findings in animal models of the human Hermansky-Pudlak syndrome (HPS), a multigenic group of recessively inherited disorders that result from abnormal synthesis of 3 related organelles: melanosomes, platelet-dense granules, and lysosomes. 7 HPS proteins regulate intracellular vesicle traffic, including the ␦ and ␤3A subunits of the AP-3 adaptor complex, which captures organelle membrane proteins at the trans-Golgi apparatus and/or endosomes, and the pallid protein, which interacts with syntaxin-13 to mediate vesicle fusion. 8,9 These HPS proteins highlight molecular pathways that serve to assemble and transport organelles but they do not overtly influence the efficiency with which MKs release platelets. In contrast, thrombocytopenia is a cardinal feature of the gunmetal mouse. 10 The cellular morphology of gm/gm MKs closely resembles that seen in the absence of NF-E2, with reduced ...

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Cell‐specific abnormal prenylation of Rab proteins in platelets and melanocytes of the gunmetal mouse

Cited by 27 publications

References 46 publications

Thematic review series: Lipid Posttranslational Modifications. Geranylgeranylation of Rab GTPases

Thematic review series: Lipid Posttranslational Modifications. Geranylgeranylation of Rab GTPases

Assembly of the Biogenesis of Lysosome-related Organelles Complex-3 (BLOC-3) and Its Interaction with Rab9

A role for Rab27b in NF-E2-dependent pathways of platelet formation

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