Proteome-level assessment of origin, prevalence and function of Leucine-Aspartic Acid (LD) motifs
Naser, Rayan Mohammad Mahmoud
Momin, Afaque Ahmad Imtiyaz
Walkiewicz, Katarzyna Wiktoria
Ali, Amal J.
Bajic, Vladimir B.
Arold, Stefan T.
KAUST DepartmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Computer Science Program
Biological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Applied Mathematics and Computational Science Program
Imaging and Characterization Core Lab
KAUST Grant NumberURF/1/1976-04
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AbstractShort Linear Motifs (SLiMs) contribute to almost every cellular function by connecting appropriate protein partners. Accurate prediction of SLiMs is difficult due to their shortness and sequence degeneracy. Leucine-aspartic acid (LD) motifs are SLiMs that link paxillin family proteins to factors controlling (cancer) cell adhesion, motility and survival. The existence and importance of LD motifs beyond the paxillin family is poorly understood. To enable a proteome-wide assessment of these motifs, we developed an active-learning based framework that iteratively integrates computational predictions with experimental validation. Our analysis of the human proteome identified a dozen proteins that contain LD motifs, all being involved in cell adhesion and migration, and revealed a new type of inverse LD motif consensus. Our evolutionary analysis suggested that LD motif signalling originated in the common unicellular ancestor of opisthokonts and amoebozoa by co-opting nuclear export sequences. Inter-species comparison revealed a conserved LD signalling core, and reveals the emergence of species-specific adaptive connections, while maintaining a strong functional focus of the LD motif interactome. Collectively, our data elucidate the mechanisms underlying the origin and adaptation of an ancestral SLiM.
CitationAlam T, Alazmi M, Naser R, Huser F, Momin AA, et al. (2018) Proteome-level assessment of origin, prevalence and function of Leucine-Aspartic Acid (LD) motifs. Available: http://dx.doi.org/10.1101/278903.
SponsorsWe acknowledge SOLEIL for provision of synchrotron radiation facilities for testing of hundreds of FAT:LD motif peptide crystals, and we would like to thank Martin Savko, Gavin Fox, William Shepard, Serena Sirigu, Leonard Chavas and Pierre Legrand for assistance in using beamlines PROXIMA I and PROXIMA IIA. We acknowledge support from the KAUST Imaging and Characterization Core Lab and the Bioscience Core Lab. We thank John Hanks and Craig Kapfer for their assistance with use of the Dragon Cluster, Robert Höhndorf for advice with the GO analysis, and Mariusz Jaremko and Lukasz Jaremko for advice with NMR data analysis. The research reported in this publication was supported by King Abdullah University of Science and Technology (KAUST) through the baseline fund and the Award No. URF/1/1976-04, URF/1/1976-06, URF/1/3007-01, URF/1/1976-02, BAS/1/1606-01-01 and #OSR-2015-CRG4-2602 from the Office of Sponsored Research (OSR).
PublisherCold Spring Harbor Laboratory
CollectionsComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division; Computer Science Program; Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Computational Bioscience Research Center (CBRC); Statistics Program; Applied Mathematics and Computational Science Program; Advanced Nanofabrication, Imaging and Characterization Core Lab; Other/General Submission
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