Publications

Authors:

Zanzoni S.; Assfalg M.; Giorgetti A.; D'Onofrio M.; Molinari H.

Title:

Structural requirements for cooperativity in ileal bile acid-binding proteins.

Year:

2011

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

A Stampa

Referee:

Sì

Name of journal:

JBC

ISSN of journal:

0021-9258

N° Volume:

286

Number or Folder:

45

Page numbers:

39307-39317

Keyword:

cooperativity; bile acid binding proteins; structure

Short description of contents:

Ileal bile acid-binding proteins (I-BABP), belonging to the family of intracellular lipid-binding proteins, control bile acid trafficking in enterocytes and participate in regulating the homeostasis of these cholesterol-derived metabolites. I-BABP orthologues share the same structural fold and are able to host up to two ligands in their large internal cavities. However variations in the primary sequences determine differences in binding properties such as the degree of binding cooperativity. To investigate the molecular requirements for cooperativity we adopted a gain-of-function approach, exploring the possibility to turn the noncooperative chicken I-BABP (cI-BABP) into a cooperative mutant protein. To this aim we first solved the solution structure of cI-BABP in complex with two molecules of the physiological ligand glycochenodeoxycholate. A comparative structural analysis with closely related members of the same protein family provided the basis to design a double mutant (H99Q/A101S cI-BABP) capable of establishing a cooperative binding mechanism. Molecular dynamics simulation studies of the wild type and mutant complexes and essential dynamics analysis of the trajectories supported the role of the identified amino acid residues as hot spot mediators of communication between binding sites. The emerging picture is consistent with a binding mechanism that can be described as an extended conformational selection model.

Product ID:

63776

Handle IRIS:

11562/373414

Deposited On:

November 16, 2011

Last Modified:

August 16, 2021

Bibliographic citation:

Zanzoni S.; Assfalg M.; Giorgetti A.; D'Onofrio M.; Molinari H., Structural requirements for cooperativity in ileal bile acid-binding proteins. «JBC» , vol. 286 , n. 45 , 2011 , pp. 39307-39317

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