A large disordered region confers a wide spanning volume to vertebrate Suppressor of Fused as shown in a trans-species solution study |
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Institution: | 1. Laboratoire de Biologie Physico-Chimique des Protéines Membranaires, Université de Paris, UMR 7099 CNRS, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005 Paris, France;2. Synchrotron SOLEIL, F-91192 Gif sur Yvette, France;3. Université de Paris, CNRS, Institut Jacques Monod, F-75006 Paris, France;4. Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005 Paris, France |
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Abstract: | Hedgehog (Hh) pathway inhibition by the conserved protein Suppressor of Fused (SuFu) is crucial to vertebrate development. By constrast, SuFu loss-of-function mutant has little effect in drosophila.Previous publications showed that the crystal structures of human and drosophila SuFu consist of two ordered domains that are capable of breathing motions upon ligand binding. However, the crystal structure of human SuFu does not give information about twenty N-terminal residues (IDR1) and an eighty-residue-long region predicted as disordered (IDR2) in the C-terminus, whose function is important for the pathway repression. These two intrinsically disordered regions (IDRs) are species-dependent.To obtain information about the IDR regions, we studied full-length SuFu’s structure in solution, both with circular dichroism and small angle X-ray scattering, comparing drosophila, zebrafish and human species, to better understand this considerable difference. Our studies show that, in spite of similar crystal structures restricted to ordered domains, drosophila and vertebrate SuFu have very different structures in solution. The IDR2 of vertebrates spans a large area, thus enabling it to reach for partners and be accessible for post-translational modifications. Furthermore, we show that the IDR2 region is highly conserved within phyla but varies in length and sequence, with insects having a shorter disordered region while that of vertebrates is broad and mobile. This major variation may explain the different phenotypes observed upon SuFu removal. |
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Keywords: | Hedgehog signal Intrinsically disordered protein Small-angle X-ray scattering |
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