The Tweety proteins are a family of recently identified putative Cl− channels predicted to be modified by N-glycosylation and, controversially, to contain five or six membrane-spanning domains, leading to the contentious proposal that members of this family do not share the same topology at the plasma membrane. In humans, three family members have been identified, designated TTYH1 (Tweety homologue 1), TTYH2 and TTYH3. To gain greater insight into the arrangement of membrane-spanning domains and cellular processing of Tweety proteins, in the present study we have examined the sequence homology, hydrophobicity and N-glycan content of members of this family and performed Nglycosylation site-mutagenesis studies on TTYH2 and TTYH3. Based on these observations we propose a structure for Tweety family proteins which incorporates five membrane-spanning domains with a topology at the cell surface in which the N-terminus is located extracellularly and the C-terminus cytoplasmically. Our results also suggest that N-glycosylation is important, but not essential, in the processing of members of the Tweety family with results indicating that, although incomplete N-glycosylation mediates reduced expression and increased ubiquitination of TTYH2, N-glycosylation is not the determining factor for TTYH2 trafficking to the plasma membrane. This information will be important for the characterization of Tweety family proteins in normal physiology and disease.

Item Type:	Refereed Article
Keywords:	Membrane protein
Research Division:	Biological Sciences
Research Group:	Biochemistry and cell biology
Research Field:	Receptors and membrane biology
Objective Division:	Health
Objective Group:	Clinical health
Objective Field:	Clinical health not elsewhere classified
UTAS Author:	Myers, SA (Dr Stephen Myers)
ID Code:	100918
Year Published:	2008
Web of Science® Times Cited:	19
Deposited By:	Health Sciences B
Deposited On:	2015-06-03
Last Modified:	2015-09-15
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