A novel tripartite motif involved in aquaporin topogenesis, monomer folding and tetramerization

Teresa M. Buck, Justin Wagner, Steven Grund, William R. Skach

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


Aquaporin (AQP) folding in the endoplasmic reticulum is characterized by two distinct pathways of membrane insertion that arise from divergent residues within the second transmembrane segment. We now show that in AQP1 these residues (Asn49 and Lys51) interact with Asp185 at the C terminus of TM5 to form a polar, quaternary structural motif that influences multiple stages of folding. Asn49 and Asp185 form an intramolecular hydrogen bond needed for proper helical packing, monomer formation and function. In contrast, Lys51 interacts with Asp185 on an adjacent monomer to stabilize the AQP1 tetramer. Although these residues are unique to AQP1, they share a highly conserved architecture whose functional properties can be transferred to other family members. These findings suggest a general mechanism by which evolutionary divergence of membrane proteins can confer new functional properties via alternative folding pathways that give rise to a common final structure.

Original languageEnglish (US)
Pages (from-to)762-769
Number of pages8
JournalNature Structural and Molecular Biology
Issue number8
StatePublished - Aug 2007
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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