Functional analysis of melanocortin-4-receptor mutants identified in severely obese subjects living in Southern Italy (Articolo in rivista)

Type
Label
  • Functional analysis of melanocortin-4-receptor mutants identified in severely obese subjects living in Southern Italy (Articolo in rivista) (literal)
Anno
  • 2010-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1016/j.gene.2010.03.001 (literal)
Alternative label
  • Alfieri, A., Pasanisi, F., Salzano, S., Esposito, L., Martone, D., Tafuri, D., Daniele, A., Contaldo, F., Sacchetti, L., Zagari, A., Buono, P (2010)
    Functional analysis of melanocortin-4-receptor mutants identified in severely obese subjects living in Southern Italy
    in Gene (Amst.)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Alfieri, A., Pasanisi, F., Salzano, S., Esposito, L., Martone, D., Tafuri, D., Daniele, A., Contaldo, F., Sacchetti, L., Zagari, A., Buono, P (literal)
Pagina inizio
  • 35 (literal)
Pagina fine
  • 41 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 457 (literal)
Rivista
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Univ Parthenope, Dipartimento Studi Ist Sistemi Terr, Fac Sci Motorie, I-80133 Naples, Italy. Fdn SDN, Ist Ricovero & Cura Carattere Sci, Naples, Italy. Univ Naples Federico 2, Dipartimento Med Clin & Sperimentale, Naples, Italy. Univ Naples Federico 2, CNR, Ist Endocrinol & Oncol Sperimentale G Salvatore, Naples, Italy. CNR, Ist Biostrutture & Bioimmagini, I-80125 Naples, Italy. Univ Molise, Dipartimento Sci Salute, Campobasso, Italy. CEINGE Biotecnol Avanzate SCaRL, Naples, Italy. Univ Naples Federico 2, Dipartimento Biochim & Biotecnol Med, Naples, Italy. (literal)
Titolo
  • Functional analysis of melanocortin-4-receptor mutants identified in severely obese subjects living in Southern Italy (literal)
Abstract
  • The melanocortin-4 receptor (MC4R) is involved in regulating energy homeostasis; mutations in this gene have been associated with 1-5% of early-onset human obesity. The aim of this study was to functionally characterize MC4R mutations identified in morbidly obese subjects living in Southern Italy. We studied their ligand binding, signaling pathway and subcellular localization. As expected, mutants Q43X and S19fsX51, which produce truncated forms of receptor, were devoid of activity. The activity of mutants W174C and A175T were very different even though the mutations are adjacent and are in the same transmembrane helix (TMH). In fact, the production and expression of mutant A175T on the plasma-membrane (PM) was similar to that of the wild-type (wt) receptor and the mutant retained 70% of wt receptor activity; on the contrary, the production of W174C mutant in the cytoplasm was similar to that of the wt receptor and mutant A175T but was only barely detectable on the PM and was devoid of activity. Confocal microscopy showed that W174C remained entrapped in the endoplasmic reticulum (ER) of the cells. Structural analysis showed that substitution of Trp174, located in the middle of TMH4 and 100% conserved in all known MC4Rs, with Cys could impair the relative orientation of TMH2 and TMH4 thereby affecting the overall protein architecture. Furthermore, co-expression studies showed that mutant A175T but not W174C had a dominant negative effect on the wt receptor activity. (literal)
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