The α/β-hydrolase fold superfamily of proteins is composed of structurally related members that, despite great diversity in their catalytic, recognition, adhesion and chaperone functions, share a common fold governed by homologous residues and conserved disulfide bridges. Non-synonymous single nucleotide polymorphisms within the α/β-hydrolase fold domain in various family members have been found for congenital endocrine, metabolic and nervous system disorders. By examining the amino acid sequence from the various proteins, mutations were found to be prevalent in conserved residues within the α/β-hydrolase fold of the homologous proteins. This is the case for the thyroglobulin mutations linked to congenital hypothyroidism. To address whether correct folding of the common domain is required for protein export, we inserted the thyroglobulin mutations at homologous positions in two correlated but simpler α/β-hydrolase fold proteins known to be exported to the cell surface: neuroligin3 and acetylcholinesterase. Here we show that these mutations in the cholinesterase homologous region alter the folding properties of the α/β-hydrolase fold domain, which are reflected in defects in protein trafficking, folding and function, and ultimately result in retention of the partially processed proteins in the endoplasmic reticulum. Accordingly, mutations at conserved residues may be transferred amongst homologous proteins to produce common processing defects despite disparate functions, protein complexity and tissue-specific expression of the homologous proteins. More importantly, a similar assembly of the α/β-hydrolase fold domain tertiary structure among homologous members of the superfamily is required for correct trafficking of the proteins to their final destination. Database A listing and description of proteins in the α/β-hydrolase fold family of proteins is available at http://bioweb.ensam.inra.fr/ESTHER/general?what= index The α/β-hydrolase fold family comprises structurally related proteins with diverse catalytic, adhesion and chaperone functions. Mutations at homologous residues in this family of proteins give rise to common trafficking alterations in endocrine function and nervous system development resulting in distinctive congenital disorders. Overlay of the α/β-hydrolase fold domain of neuroligin (yellow), thyroglobulin (green) and acetylcholinesterase (red) is represented © 2012 The Authors Journal compilation © 2012 FEBS.

Congenital hypothyroidism mutations affect common folding and trafficking in the α/β-hydrolase fold proteins / DE JACO, Antonella; Noga, Dubi; Shelley, Camp; Palmer, Taylor. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - 279:23(2012), pp. 4293-4305. [10.1111/febs.12019]

Congenital hypothyroidism mutations affect common folding and trafficking in the α/β-hydrolase fold proteins

DE JACO, Antonella;
2012

Abstract

The α/β-hydrolase fold superfamily of proteins is composed of structurally related members that, despite great diversity in their catalytic, recognition, adhesion and chaperone functions, share a common fold governed by homologous residues and conserved disulfide bridges. Non-synonymous single nucleotide polymorphisms within the α/β-hydrolase fold domain in various family members have been found for congenital endocrine, metabolic and nervous system disorders. By examining the amino acid sequence from the various proteins, mutations were found to be prevalent in conserved residues within the α/β-hydrolase fold of the homologous proteins. This is the case for the thyroglobulin mutations linked to congenital hypothyroidism. To address whether correct folding of the common domain is required for protein export, we inserted the thyroglobulin mutations at homologous positions in two correlated but simpler α/β-hydrolase fold proteins known to be exported to the cell surface: neuroligin3 and acetylcholinesterase. Here we show that these mutations in the cholinesterase homologous region alter the folding properties of the α/β-hydrolase fold domain, which are reflected in defects in protein trafficking, folding and function, and ultimately result in retention of the partially processed proteins in the endoplasmic reticulum. Accordingly, mutations at conserved residues may be transferred amongst homologous proteins to produce common processing defects despite disparate functions, protein complexity and tissue-specific expression of the homologous proteins. More importantly, a similar assembly of the α/β-hydrolase fold domain tertiary structure among homologous members of the superfamily is required for correct trafficking of the proteins to their final destination. Database A listing and description of proteins in the α/β-hydrolase fold family of proteins is available at http://bioweb.ensam.inra.fr/ESTHER/general?what= index The α/β-hydrolase fold family comprises structurally related proteins with diverse catalytic, adhesion and chaperone functions. Mutations at homologous residues in this family of proteins give rise to common trafficking alterations in endocrine function and nervous system development resulting in distinctive congenital disorders. Overlay of the α/β-hydrolase fold domain of neuroligin (yellow), thyroglobulin (green) and acetylcholinesterase (red) is represented © 2012 The Authors Journal compilation © 2012 FEBS.
2012
acetylcholinesterase; er retention; folding; neuroligin; thyroglobulin
01 Pubblicazione su rivista::01a Articolo in rivista
Congenital hypothyroidism mutations affect common folding and trafficking in the α/β-hydrolase fold proteins / DE JACO, Antonella; Noga, Dubi; Shelley, Camp; Palmer, Taylor. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - 279:23(2012), pp. 4293-4305. [10.1111/febs.12019]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/485497
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