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Phosphorylation of CFTR and Other Me...

Romeiras, Francisco Maria de Sousa de Macedo Malta,

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Phosphorylation of CFTR and Other Membrane Proteins: A Role in Biogenesis and Traffic? /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Phosphorylation of CFTR and Other Membrane Proteins: A Role in Biogenesis and Traffic? // Francisco Maria de Sousa de Macedo Malta Romeiras.
作者:	Romeiras, Francisco Maria de Sousa de Macedo Malta,
面頁冊數:	1 electronic resource (102 pages)
附註:	Source: Masters Abstracts International, Volume: 85-07.
Contained By:	Masters Abstracts International85-07.
標題:	Cystic fibrosis. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30803743
ISBN:	9798381334357

Phosphorylation of CFTR and Other Membrane Proteins: A Role in Biogenesis and Traffic? /
Romeiras, Francisco Maria de Sousa de Macedo Malta,

Phosphorylation of CFTR and Other Membrane Proteins: A Role in Biogenesis and Traffic? /Francisco Maria de Sousa de Macedo Malta Romeiras. - 1 electronic resource (102 pages)

Source: Masters Abstracts International, Volume: 85-07.

Cystic Fibrosis (CF), the most common lethal autosomal recessive disorder among Caucasians, is caused by mutations in the gene that encodes for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). With more than 1600 mutations reported, a single mutation- the deletion of phenylalanine residue at position 508 - accounts for more than 70% of chromosomes worldwide. The presence of this mutation causes CFTR retention at the endoplasmic reticulum (ER) and its early degradation at the proteasome.We have studied the effect of AMPK phosphorylation on a CFTR variant (S573C) found in non-CF patients with pancreatitis. This variant was found to be less functional than wt-CFTR and more sensitive to AMPK phosphorylation. Our results suggest that S573 plays an important role in channel gating.We have also studied the effect of CK2 phosphorylation upon CFTR function and found that TBB inhibits wt-CFTR currents without affecting F508del-CFTR. Further insight was achieved by mutating three putative CK2-phosphorylation sites. (S422, S511 and T1471). Mutating S511 (A or D) did not have any detectable effect upon wtCFTR function, while mutating S422 (A or D) significantly , decreases or increases CFTR function, respectively. Both T1471A- and T1471DCFTR are less functional than wt-CFTR, and significantly inhibitable by TBB, similarly to S422 mutants. These data suggest that CK2 may be a positive effector for CFTR biogenesis, trafficking or function.Mutating Y512, the SYK consensus phosphorylation site, into an A results in a significant increase in CFTR function in both wt- and F508del backgrounds. This mutation may cause a conformational change that favours channel gating.Altogether, these data provide novel insight into CFTR regulation by phosphorylation and thus to our understanding of the molecular mechanisms that govern its trafficking and/or function.

English

ISBN: 9798381334357Subjects--Topical Terms:

820635
Cystic fibrosis.

Phosphorylation of CFTR and Other Membrane Proteins: A Role in Biogenesis and Traffic? /
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520 $a Cystic Fibrosis (CF), the most common lethal autosomal recessive disorder among Caucasians, is caused by mutations in the gene that encodes for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). With more than 1600 mutations reported, a single mutation- the deletion of phenylalanine residue at position 508 - accounts for more than 70% of chromosomes worldwide. The presence of this mutation causes CFTR retention at the endoplasmic reticulum (ER) and its early degradation at the proteasome.We have studied the effect of AMPK phosphorylation on a CFTR variant (S573C) found in non-CF patients with pancreatitis. This variant was found to be less functional than wt-CFTR and more sensitive to AMPK phosphorylation. Our results suggest that S573 plays an important role in channel gating.We have also studied the effect of CK2 phosphorylation upon CFTR function and found that TBB inhibits wt-CFTR currents without affecting F508del-CFTR. Further insight was achieved by mutating three putative CK2-phosphorylation sites. (S422, S511 and T1471). Mutating S511 (A or D) did not have any detectable effect upon wtCFTR function, while mutating S422 (A or D) significantly , decreases or increases CFTR function, respectively. Both T1471A- and T1471DCFTR are less functional than wt-CFTR, and significantly inhibitable by TBB, similarly to S422 mutants. These data suggest that CK2 may be a positive effector for CFTR biogenesis, trafficking or function.Mutating Y512, the SYK consensus phosphorylation site, into an A results in a significant increase in CFTR function in both wt- and F508del backgrounds. This mutation may cause a conformational change that favours channel gating.Altogether, these data provide novel insight into CFTR regulation by phosphorylation and thus to our understanding of the molecular mechanisms that govern its trafficking and/or function.
520 $a A fibrose quistica e a doenca autossomica recessiva mais comum na populacao caucasiana, com uma incidencia de 1:2500. Esta doenca monogenica letal e caracterizada pela producao de muco extremamente espesso pelas celulas epiteliais que revestem os pulmoes, que leva consequentemente a obstrucao das vias aereas e ao aparecimento recorrente de infeccoes bacterianas. A perda de funcao pulmonar e responsavel por 95% da mortalidade. Alem disso, a fibrose quistica e tambem caracterizada por insuficiencia pancreatica exocrina, infertilidade masculina e funcionamento incorrecto das glandulas sudoriparas - elevando a concentracao de electrolitos no suor, observacao que esta na base do mais classico metodo de diagnostico da doenca - o teste do suor.Tanto a esperanca media de vida como a qualidade de vida dos doentes de fibrose quistica tem vindo a aumentar nos ultimos anos, sobretudo devido aos avancos no controlo dos sintomas desta doenca, sobretudo, incluindo fisioterapia, administracao de antibioticos e suplementos enzimaticos.A base molecular desta doenca foi elucidada em 1989 com a clonagem do gene que codifica para a proteina CFTR (Cystic Fibrosis Transmembrane Conductance Regulator). Esta proteina pertence a familia dos transportadores ABC (ATP-binding cassette) e funciona como canal de cloreto activado por cAMP e PKA (Protein Kinase A), na membrana apical de celulas epiteliais.A ausencia de secrecao de cloreto pela proteina CFTR e a hiperabsorcao de sodio atraves do canal epitelial de sodio (ENaC) levam a um aumento da absorcao de agua e consequente desidratacao do muco que reveste as vias aereas, aumentando a sua viscosidade e facilitando a colonizacao bacteriana. Desta forma, o organismo tende a desenvolver uma resposta inflamatoria continua, levando a uma perda progressiva da funcao pulmonar e, em ultima analise, a morte.Dados mais recentes indicam que a CFTR esta tambem envolvida na secrecao de bicarbonato pelas celulas do ducto pancreatico, apesar do mecanismo exacto pelo qual actua nao ser consensual. A secrecao de bicarbonato pode ocorrer directamente atraves da CFTR ou atraves da troca com cloreto, que sera continuamente secretado pela CFTR para o lumen do ducto pancreatico.A CFTR contem 1480 residuos de aminoacidos e e constituida por 5 dominios: 2 dominios transmembranares (TMD) que formam o canal ionico, 2 dominios de ligacao a nucleotidos (NBD), cada um com a capacidade de ligar uma molecula de ATP, essenciais para a abertura do canal, e um dominio de regulacao (R), fosforilado por diversos cinases e principal responsavel na regulacao da funcao da CFTR.
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650 4 $a Mutation. $3 837917
650 4 $a Adenosine triphosphate. $3 3331834
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710 2 $a Universidade de Lisboa (Portugal). $e degree granting institution. $3 3759222
720 1 $a Farinha, Carlos $e degree supervisor.
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