IGF-dependent dynamic modulation of a protease cleavage site in the intrinsically disordered linker domain of human IGFBP2.
Proteins
; 90(9): 1732-1743, 2022 09.
Article
en En
| MEDLINE
| ID: mdl-35443068
ABSTRACT
Functional regulation via conformational dynamics is well known in structured proteins but less well characterized in intrinsically disordered proteins and their complexes. Using NMR spectroscopy, we have identified a dynamic regulatory mechanism in the human insulin-like growth factor (IGF) system involving the central, intrinsically disordered linker domain of human IGF-binding protein-2 (hIGFBP2). The bioavailability of IGFs is regulated by the proteolysis of IGF-binding proteins. In the case of hIGFBP2, the linker domain (L-hIGFBP2) retains its intrinsic disorder upon binding IGF-1, but its dynamics are significantly altered, both in the IGF binding region and distantly located protease cleavage sites. The increase in flexibility of the linker domain upon IGF-1 binding may explain the IGF-dependent modulation of proteolysis of IGFBP2 in this domain. As IGF homeostasis is important for cell growth and function, and its dysregulation is a key contributor to several cancers, our findings open up new avenues for the design of IGFBP analogs inhibiting IGF-dependent tumors.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factor I del Crecimiento Similar a la Insulina
/
Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina
/
Proteínas Intrínsecamente Desordenadas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Proteins
Asunto de la revista:
BIOQUIMICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
India