PT  - JOURNAL ARTICLE
AU  - Tanvir Alam
AU  - Meshari Alazmi
AU  - Rayan Naser
AU  - Franceline Huser
AU  - Afaque A. Momin
AU  - Katarzyna W. Walkiewicz
AU  - Christian G. Canlas
AU  - Raphaël G. Huser
AU  - Amal J. Ali
AU  - Jasmeen Merzaban
AU  - Vladimir B. Bajic
AU  - Xin Gao
AU  - Stefan T. Arold
TI  - Proteome-level assessment of origin, prevalence and function of Leucine-Aspartic Acid (LD) motifs
AID  - 10.1101/278903
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 278903
4099  - http://biorxiv.org/content/early/2018/03/10/278903.short
4100  - http://biorxiv.org/content/early/2018/03/10/278903.full
AB  - Short 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.