title: Three-dimensional structure and stability of the KH domain: molecular insights into the fragile X syndrome.
abstract: The KH module is a sequence motif found in a number of proteins that are known to be in close association with RNA. Experimental evidence suggests a direct involvement of KH in RNA binding. The human FMR1 protein, which has two KH domains, is associated with fragile X syndrome, the most common inherited cause of mental retardation. Here we present the three-dimensional solution structure of the KH module. The domain consists of a stable beta alpha alpha beta beta alpha fold. On the basis of our results, we suggest a potential surface for RNA binding centered on the loop between the first two helices. Substitution of a well-conserved hydrophobic residue located on the second helix destroys the KH fold; a mutation of this position in FMR1 leads to an aggravated fragile X phenotype.
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Federal Republic of Germany.
authors.forename: G
authors.initials: G
authors.lastname: Musco
authors.forename: G
authors.initials: G
authors.lastname: Stier
authors.forename: C
authors.initials: C
authors.lastname: Joseph
authors.forename: M A
authors.initials: MA
authors.lastname: Castiglione Morelli
authors.forename: M
authors.initials: M
authors.lastname: Nilges
authors.forename: T J
authors.initials: TJ
authors.lastname: Gibson
authors.forename: A
authors.initials: A
authors.lastname: Pastore
mesh_terms: D001216:Asparagine / Q000235:genetics; D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D016601:RNA-Binding Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid
chemical_list: D002352:Carrier Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D007532:Isoleucine; C075197:high density lipoprotein binding protein; D001216:Asparagine