A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype

Hyun Jin Kim, Qin Li, Sandra Tjon-Kon-Sang, Insuk So, Kirill Kiselyov, Abigail A. Soyombo, Shmuel Muallem

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

TRPML3 belongs to the TRPML subfamily of the transient receptor potential (TRP) channels. The A419P mutation in TRPML3 causes the varitint-waddler phenotype as a result of gain-of-function mutation (GOF). Regulation of the channels and the mechanism by which the A419P mutation leads to GOF are not known. We report here that TRPML3 is a Ca2+-permeable channel with a unique form of regulation by extracytosolic (luminal) H+ (H + e-cyto). Regulation by H+ e-cyto is mediated by a string of three histidines (H252, H273, H283) in the large extracytosolic loop between transmembrane domains (TMD) 1 and 2. Each of the histidines has a unique role, whereby H252 and H273 retard access of H + e-cyto to the inhibitory H283. Notably, the H283A mutation has the same phenotype as A419P and locks the channel in an open state, whereas the H283R mutation inactivates the channel. Accordingly, A419P eliminates regulation of TRPML3 by H+ e-cyto, and confers full activation to TRPML3(H283R). Activation of TRPML3 and regulation by H + e-cyto are altered by both the α-helix- destabilizing A419G and the α-helix-favouring A419M and A419K. These findings suggest that regulation of TRPML3 by H+ e-cyto is due to an effect of the large extracytosolic loop on the orientation of fifth TMD and thus pore opening and show that the GOF of TRPML3(A419P) is due to disruption of this communication.

Original languageEnglish (US)
Pages (from-to)1197-1205
Number of pages9
JournalEMBO Journal
Volume27
Issue number8
DOIs
StatePublished - Apr 23 2008

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Phenotype
Histidine
Mutation
Chemical activation
Transient Receptor Potential Channels
Communication

Keywords

  • Extracytosolic loop
  • Extracytosolic pH
  • Histidines string
  • TRPML3
  • Varitint-waddler phenotype

ASJC Scopus subject areas

  • Genetics
  • Cell Biology
  • Medicine(all)

Cite this

Kim, H. J., Li, Q., Tjon-Kon-Sang, S., So, I., Kiselyov, K., Soyombo, A. A., & Muallem, S. (2008). A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype. EMBO Journal, 27(8), 1197-1205. https://doi.org/10.1038/emboj.2008.56

A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype. / Kim, Hyun Jin; Li, Qin; Tjon-Kon-Sang, Sandra; So, Insuk; Kiselyov, Kirill; Soyombo, Abigail A.; Muallem, Shmuel.

In: EMBO Journal, Vol. 27, No. 8, 23.04.2008, p. 1197-1205.

Research output: Contribution to journalArticle

Kim, HJ, Li, Q, Tjon-Kon-Sang, S, So, I, Kiselyov, K, Soyombo, AA & Muallem, S 2008, 'A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype', EMBO Journal, vol. 27, no. 8, pp. 1197-1205. https://doi.org/10.1038/emboj.2008.56
Kim HJ, Li Q, Tjon-Kon-Sang S, So I, Kiselyov K, Soyombo AA et al. A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype. EMBO Journal. 2008 Apr 23;27(8):1197-1205. https://doi.org/10.1038/emboj.2008.56
Kim, Hyun Jin ; Li, Qin ; Tjon-Kon-Sang, Sandra ; So, Insuk ; Kiselyov, Kirill ; Soyombo, Abigail A. ; Muallem, Shmuel. / A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype. In: EMBO Journal. 2008 ; Vol. 27, No. 8. pp. 1197-1205.
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abstract = "TRPML3 belongs to the TRPML subfamily of the transient receptor potential (TRP) channels. The A419P mutation in TRPML3 causes the varitint-waddler phenotype as a result of gain-of-function mutation (GOF). Regulation of the channels and the mechanism by which the A419P mutation leads to GOF are not known. We report here that TRPML3 is a Ca2+-permeable channel with a unique form of regulation by extracytosolic (luminal) H+ (H + e-cyto). Regulation by H+ e-cyto is mediated by a string of three histidines (H252, H273, H283) in the large extracytosolic loop between transmembrane domains (TMD) 1 and 2. Each of the histidines has a unique role, whereby H252 and H273 retard access of H + e-cyto to the inhibitory H283. Notably, the H283A mutation has the same phenotype as A419P and locks the channel in an open state, whereas the H283R mutation inactivates the channel. Accordingly, A419P eliminates regulation of TRPML3 by H+ e-cyto, and confers full activation to TRPML3(H283R). Activation of TRPML3 and regulation by H + e-cyto are altered by both the α-helix- destabilizing A419G and the α-helix-favouring A419M and A419K. These findings suggest that regulation of TRPML3 by H+ e-cyto is due to an effect of the large extracytosolic loop on the orientation of fifth TMD and thus pore opening and show that the GOF of TRPML3(A419P) is due to disruption of this communication.",
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