#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Mutations in or near the Transmembrane Domain Alter PMEL Amyloid Formation from Functional to Pathogenic


PMEL is a pigment cell-specific protein that forms physiological amyloid fibrils upon which melanins ultimately deposit in the lumen of the pigment organelle, the melanosome. Whereas hypomorphic PMEL mutations in several species result in a mild pigment dilution that is inherited in a recessive manner, PMEL alleles found in the Dominant white (DW) chicken and Silver horse (HoSi)—which bear mutations that alter the PMEL transmembrane domain (TMD) and that are thus outside the amyloid core—are associated with a striking loss of pigmentation that is inherited in a dominant fashion. Here we show that the DW and HoSi mutations alter PMEL TMD oligomerization and/or association with membranes, with consequent formation of aberrantly packed fibrils. The aberrant fibrils are associated with a loss of pigmentation in cultured melanocytes, suggesting that they inhibit melanin production and/or melanosome integrity. A secondary mutation in the Smoky chicken, which reverts the dominant DW phenotype, prevents the accumulation of PMEL in fibrillogenic compartments and thus averts DW–associated pigment loss; a secondary mutation found in the Dun chicken likely dampens a HoSi–like dominant mutation in a similar manner. We propose that the DW and HoSi mutations alter the normally benign amyloid to a pathogenic form that antagonizes melanosome function, and that the secondary mutations found in the Smoky and Dun chickens revert or dampen pathogenicity by functioning as null alleles, thus preventing the formation of aberrant fibrils. We speculate that PMEL mutations can model the conversion between physiological and pathological amyloid.


Vyšlo v časopise: Mutations in or near the Transmembrane Domain Alter PMEL Amyloid Formation from Functional to Pathogenic. PLoS Genet 7(9): e32767. doi:10.1371/journal.pgen.1002286
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002286

Souhrn

PMEL is a pigment cell-specific protein that forms physiological amyloid fibrils upon which melanins ultimately deposit in the lumen of the pigment organelle, the melanosome. Whereas hypomorphic PMEL mutations in several species result in a mild pigment dilution that is inherited in a recessive manner, PMEL alleles found in the Dominant white (DW) chicken and Silver horse (HoSi)—which bear mutations that alter the PMEL transmembrane domain (TMD) and that are thus outside the amyloid core—are associated with a striking loss of pigmentation that is inherited in a dominant fashion. Here we show that the DW and HoSi mutations alter PMEL TMD oligomerization and/or association with membranes, with consequent formation of aberrantly packed fibrils. The aberrant fibrils are associated with a loss of pigmentation in cultured melanocytes, suggesting that they inhibit melanin production and/or melanosome integrity. A secondary mutation in the Smoky chicken, which reverts the dominant DW phenotype, prevents the accumulation of PMEL in fibrillogenic compartments and thus averts DW–associated pigment loss; a secondary mutation found in the Dun chicken likely dampens a HoSi–like dominant mutation in a similar manner. We propose that the DW and HoSi mutations alter the normally benign amyloid to a pathogenic form that antagonizes melanosome function, and that the secondary mutations found in the Smoky and Dun chickens revert or dampen pathogenicity by functioning as null alleles, thus preventing the formation of aberrant fibrils. We speculate that PMEL mutations can model the conversion between physiological and pathological amyloid.


Zdroje

1. ChitiFDobsonCM 2006 Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75 333 366

2. GreenwaldJRiekR 2010 Biology of amyloid: structure, function, and regulation. Structure 18 1244 1260

3. FowlerDMKoulovAVBalchWEKellyJW 2007 Functional amyloid--from bacteria to humans. Trends Biochem Sci 32 217 224

4. MajiSKPerrinMHSawayaMRJessbergerSVadodariaK 2009 Functional amyloids as natural storage of peptide hormones in pituitary secretory granules. Science 325 328 332

5. WicknerRBShewmakerFKryndushkinDEdskesHK 2008 Protein inheritance (prions) based on parallel in-register beta-sheet amyloid structures. Bioessays 30 955 964

6. HammerNDWangXMcGuffieBAChapmanMR 2008 Amyloids: friend or foe? J Alzheimers Dis 13 407 419

7. TheosACTruschelSTRaposoGMarksMS 2005 The Silver locus product Pmel17/ gp100/ Silv/ ME20: Controversial in name and in function. Pigment Cell Res 18 322 336

8. WattBRaposoGMarksMS 2010 Pmel17: An amyloid determinant of organelle structure. BucciantiniM Functional Amyloid Aggregation Trivandrum, Kerala, India Research Signpost

9. HearingVJ 2005 Biogenesis of pigment granules: a sensitive way to regulate melanocyte function. J Dermatol Sci 37 3 14

10. RaposoGMarksMS 2007 Melanosomes - dark organelles enlighten endosomal membrane transport. Nat Rev Mol Cell Biol 8 786 798

11. HurbainIGeertsWJCBoudierTMarcoSVerkleijA 2008 Electron tomography of early melanosomes: implications for melanogenesis and the generation of fibrillar amyloid sheets. Proc Natl Acad Sci USA 105 19726 19731

12. HarperDCTheosACHermanKETenzaDRaposoG 2008 Premelanosome amyloid-like fibrils are composed of only golgi-processed forms of pmel17 that have been proteolytically processed in endosomes. J Biol Chem 283 2307 2322

13. BersonJFHarperDTenzaDRaposoGMarksMS 2001 Pmel17 initiates premelanosome morphogenesis within multivesicular bodies. Mol Biol Cell 12 3451 3464

14. RaposoGTenzaDMurphyDMBersonJFMarksMS 2001 Distinct protein sorting and localization to premelanosomes, melanosomes, and lysosomes in pigmented melanocytic cells. J Cell Biol 152 809 823

15. LeonhardtRMVigneronNRahnerCCresswellP 2011 Proprotein convertases process Pmel17 during secretion. J Biol Chem 286 9321 9337

16. TheosACTruschelSTTenzaDHurbainIHarperDC 2006 A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. Dev Cell 10 343 354

17. BersonJFTheosACHarperDCTenzaDRaposoG 2003 Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis. J Cell Biol 161 521 533

18. KummerMPMaruyamaHHuelsmannCBachesSWeggenS 2009 Formation of Pmel17 amyloid is regulated by juxtamembrane metalloproteinase cleavage, and the resulting C-terminal fragment is a substrate for gamma-secretase. J Biol Chem 284 2296 2306

19. FowlerDMKoulovAVAlory-JostCMarksMSBalchWE 2006 Functional amyloid formation within mammalian tissue. PLoS Biol 4 e6 doi:10.1371/journal.pbio.0040006

20. ChiamentiAMVellaFBonettiFPeaMFerrariS 1996 Anti-melanoma monoclonal antibody HMB-45 on enhanced chemiluminescence-western blotting recognizes a 30-35 kDa melanosome-associated sialated glycoprotein. Melanoma Res 6 291 298

21. KushimotoTBasrurVValenciaJMatsunagaJVieiraWD 2001 A model for melanosome biogenesis based on the purification and analysis of early melanosomes. Proc Natl Acad Sci USA 98 10698 10703

22. HoashiTMullerJVieiraWDRouzaudFKikuchiK 2006 The repeat domain of the melanosomal matrix protein Pmel17/gp100 is required for the formation of organellar fibers. J Biol Chem 281 21198 22208

23. WattBvan NielGFowlerDMHurbainILukKC 2009 N-terminal domains elicit formation of functional Pmel17 amyloid fibrils. J Biol Chem 284 35543 35555

24. SeijiMFitzpatrickTMSimpsonRTBirbeckMSC 1963 Chemical composition and terminology of specialized organelles (melanosomes and melanin granules) in mammalian melanocytes. Nature 197 1082 1084

25. McGlincheyRPShewmakerFMcPhiePMonterrosoBThurberK 2009 The repeat domain of the melanosome fibril protein Pmel17 forms the amyloid core promoting melanin synthesis. Proc Natl Acad Sci USA 106 13731 13736

26. DunnLCThigpenLW 1930 The silver mouse: a recessive color variation. J Heredity 21 495 498

27. ClarkLAWahlJMReesCAMurphyKE 2006 Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proc Natl Acad Sci USA 103 1376 1381

28. SchonthalerHBLampertJMvon LintigJSchwarzHGeislerR 2005 A mutation in the silver gene leads to defects in melanosome biogenesis and alterations in the visual system in the zebrafish mutant fading vision. Dev Biol 284 421 436

29. HellströmARWattBFardSSTenzaDMannströmP 2011 Inactivation of the Pmel gene alters melanosome shape but has only a subtle effect on visible pigmentation. PLoS Genet 7 e1002285 doi:10.1371/journal.pgen.1002285

30. KerjeSSharmaPGunnarssonUKimHBagchiS 2004 The Dominant white, Dun and Smoky color variants in chicken are associated with insertion deletion polymorphisms in the PMEL17 gene. Genetics 168 1507 1518

31. HamiltonH 1940 A study of the physiological properties of melanophores with special reference to their role in feather coloration. Anat Rec 78 525 548

32. SpanakisELaminaPBennettDC 1992 Effects of the developmental colour mutations silver and recessive spotting on proliferation of diploid and immortal mouse melanocytes in culture. Development 114 675 680

33. QuevedoWCFleischmannRDDyckmanJ 1981 Premature loss of melanocytes from hair follicles of light (Blt) and silver (si) mice. SeijiM Phenotypic expression in pigment cells Tokyo Tokyo Univ Press 177 184

34. BrumbaughJA 1971 The ultrastructural effects of the I and S loci upon black-red melanin differentiation in the fowl. Dev Biol 24 392 412

35. BrumbaughJALeeKW 1975 The gene action and function of two dopa oxidase positive melanocyte mutants of the fowl. Genetics 81 333 347

36. BrunbergEAnderssonLCothranGSandbergKMikkoS 2006 A missense mutation in PMEL17 is associated with the Silver coat color in the horse. BMC Genet 7 46

37. ReissmannMBierwolfJBrockmannGA 2007 Two SNPs in the SILV gene are associated with silver coat colour in ponies. Anim Genet 38 1 6

38. KuliawatRSantambrogioL 2009 A mutation within the transmembrane domain of melanosomal protein Silver (Pmel17) changes lumenal fragment interactions. Eur J Cell Biol 88 653 667

39. RussWPEngelmanDM 1999 TOXCAT: a measure of transmembrane helix association in a biological membrane. Proc Natl Acad Sci USA 96 863 868

40. ShawWV 1975 Chloramphenicol acetyltransferase from chloramphenicol-resistant bacteria. Methods Enzymol 43 737 755

41. LemmonMATreutleinHRAdamsPDBrüngerATEngelmanDM 1994 A dimerization motif for transmembrane alpha-helices. Nat Struct Biol 1 157 163

42. DonatienPDOrlowSJ 1995 Interaction of melanosomal proteins with melanin. Eur J Biochem 232 159 164

43. CossonPBonifacinoJS 1992 Role of transmembrane domain interactions in the assembly of class II MHC molecules. Science 258 659 662

44. MendrolaJMBergerMBKingMCLemmonMA 2002 The single transmembrane domains of ErbB receptors self-associate in cell membranes. J Biol Chem 277 4704 4712

45. MunterL-MVoigtPHarmeierAKadenDGottschalkKE 2007 GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42. EMBO J 26 1702 1712

46. NgDPDeberCM 2010 Modulation of the oligomerization of myelin proteolipid protein by transmembrane helix interaction motifs. Biochemistry 49 6896 6902

47. RutledgeTCossonPManoliosNBonifacinoJSKlausnerRD 1992 Transmembrane helical interactions: zeta chain dimerization and functional association with the T cell antigen receptor. Embo J 11 3245 3254

48. TannerKGKyteJ 1999 Dimerization of the extracellular domain of the receptor for epidermal growth factor containing the membrane-spanning segment in response to treatment with epidermal growth factor. J Biol Chem 274 35985 35990

49. EhehaltRKellerPHaassCThieleCSimonsK 2003 Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts. J Cell Biol 160 113 123

50. TheosACTenzaDMartinaJAHurbainIPedenAA 2005 Functions of AP-3 and AP-1 in tyrosinase sorting from endosomes to melanosomes. Mol Biol Cell 16 5356 5372

51. SamuelsonDASmithPUlshaferRJHendricksDGWhitleyRD 1993 X-ray microanalysis of ocular melanin in pigs maintained on normal and low zinc diets. Exp Eye Res 56 63 70

52. SzekeresL 1975 Fine structure and X-ray microanalysis of melanosomes in pigmented nevi and melanomas. Arch Derm Forsch 252 297 304

53. ZarebaMSzewczykGSarnaTHongLSimonJD 2006 Effects of photodegradation on the physical and antioxidant properties of melanosomes isolated from retinal pigment epithelium. Photochem Photobiol 82 1024 1029

54. ChakrabortyAKPlattJTKimKKKwonBSBennettDC 1996 Polymerization of 5,6-dihydroxyindole-2-carboxylic acid to melanin by the pmel 17/silver locus protein. Eur J Biochem 236 180 188

55. SettySRGTenzaDSviderskayaEVBennettDCRaposoG 2008 Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes. Nature 454 1142 1146

56. GorbenkoGPKinnunenPK 2006 The role of lipid-protein interactions in amyloid-type protein fibril formation. Chem Phys Lipids 141 72 82

57. SviderskayaEVHillSPEvans-WhippTJChinLOrlowSJ 2002 p16Ink4a in melanocyte senescence and differentiation. J Natl Cancer Inst 94 446 454

58. SettySRGTenzaDTruschelSTChouESviderskayaEV 2007 BLOC-1 is required for cargo-specific sorting from vacuolar early endosomes toward lysosome-related organelles. Mol Biol Cell 18 768 780

59. RaposoGKleijmeerMJPosthumaGSlotJWGeuzeHJ 1997 Immunogold labeling of ultrathin cryosections: application in immunology. HerzenbergLAWeirDHerzenbergLABlackwellC Handbook of Exp Immunol Cambridge, MA Blackwell Science, Inc 1 11 5th ed.

60. BersonJFFrankDWCalvoPABielerBMMarksMS 2000 A common temperature-sensitive allelic form of human tyrosinase is retained in the endoplasmic reticulum at the nonpermissive temperature. J Biol Chem 275 12281 12289

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2011 Číslo 9
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#