Genetics, Vol. 166, 1323-1336, March 2004, Copyright © 2004

Cysteine Repeat Domains and Adjacent Sequences Determine Distinct Bone Morphogenetic Protein Modulatory Activities of the Drosophila Sog Protein

Kweon Yua,b, Kyung-Hwa Kanga, Petra Heinea, Ujwal Pyatic, Shaila Srinivasana,d, Brian Biehsa,e, David Kimelmanc, and Ethan Biera
a Section of Cell and Developmental Biology and Center for Molecular Genetics, University of California, San Diego, California 92093-0349,
b Laboratory of Development and Differentiation, Korea Research Institute of Bioscience and Biotechnology, Yusong-gu, Daejon, 305-333, Korea,
c Department of Biochemistry, University of Washington, Seattle, Washington 98195-7530,
d University of Illinois, Chicago, Illinois 60607
e University of California, San Francisco, California 94143-0448

Corresponding author: Ethan Bier, University of California, San Diego, California 92093-0349., bier{at}biomail.ucsd.edu (E-mail)

Communicating editor: D. WEIGEL

The Drosophila short gastrulation gene (sog) encodes a large extracellular protein (Sog) that inhibits signaling by BMP-related ligands. Sog and its vertebrate counterpart Chordin contain four copies of a cysteine repeat (CR) motif defined by 10 cysteine residues spaced in a fixed pattern and a tryptophan residue situated between the first two cysteines. Here we present a structure-function analysis of the CR repeats in Sog, using a series of deletion and point mutation constructs, as well as constructs in which CR domains have been swapped. This analysis indicates that the CR domains are individually dispensable for Sog function but that they are not interchangeable. These studies reveal three different types of Sog activity: intact Sog, which inhibits signaling mediated by the ligand Glass bottom boat (Gbb), a more broadly active class of BMP antagonist referred to as Supersog, and a newly identified activity, which may promote rather than inhibit BMP signaling. Analysis of the activities of CR swap constructs indicates that the CR domains are required for full activity of the various forms of Sog but that the type of Sog activity is determined primarily by surrounding protein sequences. Cumulatively, our analysis suggests that CR domains interact physically with adjacent protein sequences to create forms of Sog with distinct BMP modulatory activities.




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