TY - JOUR
T1 - Proteome-level assessment of origin, prevalence and function of Leucine-Aspartic Acid (LD) motifs.
AU - Alam, Tanvir
AU - Alazmi, Meshari
AU - Naser, Rayan Mohammad Mahmoud
AU - Huser, Franceline
AU - Momin, Afaque Ahmad Imtiyaz
AU - Astro, Veronica
AU - Hong, Seungbeom
AU - Walkiewicz, Katarzyna Wiktoria
AU - Canlas, Christian G
AU - Huser, Raphaël
AU - Ali, Amal J.
AU - Merzaban, Jasmeen
AU - Adamo, Antonio
AU - Jaremko, Mariusz
AU - Jaremko, Lukasz
AU - Bajic, Vladimir B.
AU - Gao, Xin
AU - Arold, Stefan T.
N1 - KAUST Repository Item: Exported on 2020-10-01
Acknowledged KAUST grant number(s): URF/1/1976-04, URF/1/3007-01, URF/1/1976-02, BAS/1/1606-01-01, OSR-2015- CRG4-2602
Acknowledgements: We acknowledge SOLEIL for provision of synchrotron radiation facilities for testing of FAT:LD motif peptide crystals. We thank M. Savko, W. Shepard, S. Sirigu, L. Chavas and P. Legrand for assistance in using beamlines PX1 and PX2A. We thank R. Höhndorf for advice with the GO analysis, J. Hanks, C. Kapfer and A. Hungler for help with computing at KAUST. We acknowledge support from the KAUST Imaging and Characterization Core Lab, the Bioscience Core Lab and Research Computing Core lab.
PY - 2019/10/4
Y1 - 2019/10/4
N2 - MOTIVATION:Leucine-aspartic acid (LD) motifs are short linear interaction motifs (SLiMs) that link paxillin family proteins to factors controlling cell adhesion, motility and survival. The existence and importance of LD motifs beyond the paxillin family is poorly understood. RESULTS:To enable a proteome-wide assessment of LD motifs, we developed an active-learning based framework (LDmotif finder; LDMF) that iteratively integrates computational predictions with experimental validation. Our analysis of the human proteome revealed a dozen new proteins containing LD motifs. We found that LD motif signalling evolved in unicellular eukaryotes more than 800 Myr ago, with paxillin and vinculin as core constituents, and nuclear export signal (NES) as a likely source of de novo LD motifs. We show that LD motif proteins form a functionally homogenous group, all being involved in cell morphogenesis and adhesion. This functional focus is recapitulated in cells by GFP-fused LD motifs, suggesting that it is intrinsic to the LD motif sequence, possibly through their effect on binding partners. Our approach elucidated the origin and dynamic adaptations of an ancestral SLiM, and can serve as a guide for the identification of other SLiMs for which only few representatives are known. AVAILABILITY:LDMF is freely available online at www.cbrc.kaust.edu.sa/ldmf; Source code is available at https://github.com/tanviralambd/LD/. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.
AB - MOTIVATION:Leucine-aspartic acid (LD) motifs are short linear interaction motifs (SLiMs) that link paxillin family proteins to factors controlling cell adhesion, motility and survival. The existence and importance of LD motifs beyond the paxillin family is poorly understood. RESULTS:To enable a proteome-wide assessment of LD motifs, we developed an active-learning based framework (LDmotif finder; LDMF) that iteratively integrates computational predictions with experimental validation. Our analysis of the human proteome revealed a dozen new proteins containing LD motifs. We found that LD motif signalling evolved in unicellular eukaryotes more than 800 Myr ago, with paxillin and vinculin as core constituents, and nuclear export signal (NES) as a likely source of de novo LD motifs. We show that LD motif proteins form a functionally homogenous group, all being involved in cell morphogenesis and adhesion. This functional focus is recapitulated in cells by GFP-fused LD motifs, suggesting that it is intrinsic to the LD motif sequence, possibly through their effect on binding partners. Our approach elucidated the origin and dynamic adaptations of an ancestral SLiM, and can serve as a guide for the identification of other SLiMs for which only few representatives are known. AVAILABILITY:LDMF is freely available online at www.cbrc.kaust.edu.sa/ldmf; Source code is available at https://github.com/tanviralambd/LD/. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.
UR - http://hdl.handle.net/10754/658612
UR - https://academic.oup.com/bioinformatics/advance-article/doi/10.1093/bioinformatics/btz703/5581347
UR - http://www.scopus.com/inward/record.url?scp=85080845558&partnerID=8YFLogxK
U2 - 10.1093/bioinformatics/btz703
DO - 10.1093/bioinformatics/btz703
M3 - Article
C2 - 31584626
VL - 36
SP - 1121
EP - 1128
JO - Bioinformatics
JF - Bioinformatics
SN - 1367-4803
IS - 4
ER -