A novel carcinogenic PI3Kα mutation suggesting the role of helical domain in transmitting nSH2 regulatory signals to kinase domain.
Life Sci
; 269: 118759, 2021 Mar 15.
Article
en En
| MEDLINE
| ID: mdl-33189828
ABSTRACT
AIMS:
Mutations in PIK3CA, which encodes p110α subunit of PI3K class IA enzymes, are highly frequent in breast cancer. Here, we aimed to probe mutations in exon 9 of PIK3CA and computationally simulate their function. MATERIALS ANDMETHODS:
PCR/HRM and PCR/sequencing were used for mutation detection in 40 breast cancer specimens. The identified mutations were queried via in silico algorithms to check the pathogenicity. The molecular dynamics (MD) simulations were utilized to assess the function of mutant proteins. KEYFINDINGS:
Three samples were found to harbor at least one of the E542K, E545K and L551Q mutations of which L551Q has not been reported previously. All mutations were confirmed to be pathogenic and MD simulations revealed their impact on protein function and regulation. The novel L551Q mutant dynamics was similar to that of previously found carcinogenic mutants, E542K and E545K. A functional role for the helical domain was also suggested by which the inhibitory signal of p85α is conducted to kinase domain via helical domain. Helical domain mutations lead to impairment of kinase domain allosteric regulation. Interestingly, our results show that p110α substrate binding pocket of kinase domain in mutants may have differential affinity for enzyme substrates, including anit-p110α drugs.SIGNIFICANCE:
The novel p110α L551Q mutation could have carcinogenic feature similar to previously known helical domain mutations.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Fosfatidilinositol 3-Quinasa Clase I
/
Carcinogénesis
/
Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Female
/
Humans
/
Middle aged
Idioma:
En
Revista:
Life Sci
Año:
2021
Tipo del documento:
Article
País de afiliación:
Irán