A conformational switch in the Piccolo C2A domain regulated by alternative splicing

Jesus Garcia, Stefan H. Gerber, Shuzo Sugita, Thomas C. Südhof, Jose Rizo-Rey

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

C2 domains are widespread Ca2+-binding modules. The active zone protein Piccolo (also known as Aczonin) contains an unusual C 2A domain that exhibits a low affinity for Ca2+, a Ca 2+-induced conformational change and Ca2+-dependent dimerization. We show here that removal of a nine-residue sequence by alternative splicing increases the Ca2+ affinity, abolishes the conformational change and abrogates dimerization of the Piccolo C2A domain. The NMR structure of the Ca2+-free long variant provides a structural basis for these different properties of the two splice forms, showing that the nine-residue sequence forms a β-strand otherwise occupied by a nonspliced sequence. Consequently, Ca2+-binding to the long Piccolo C2A domain requires a marked rearrangement of secondary structure that cannot occur for the short variant. These results reveal a novel mechanism of action of C2 domains and uncover a structural principle that may underlie the alteration of protein function by short alternatively spliced sequences.

Original languageEnglish (US)
Pages (from-to)45-53
Number of pages9
JournalNature Structural and Molecular Biology
Volume11
Issue number1
DOIs
StatePublished - Jan 2004

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Alternative Splicing
Dimerization
Proteins
C2 Domains

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

A conformational switch in the Piccolo C2A domain regulated by alternative splicing. / Garcia, Jesus; Gerber, Stefan H.; Sugita, Shuzo; Südhof, Thomas C.; Rizo-Rey, Jose.

In: Nature Structural and Molecular Biology, Vol. 11, No. 1, 01.2004, p. 45-53.

Research output: Contribution to journalArticle

Garcia, Jesus ; Gerber, Stefan H. ; Sugita, Shuzo ; Südhof, Thomas C. ; Rizo-Rey, Jose. / A conformational switch in the Piccolo C2A domain regulated by alternative splicing. In: Nature Structural and Molecular Biology. 2004 ; Vol. 11, No. 1. pp. 45-53.
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