Systematic In Silico Discovery of a Conserved Tubulin-Folding Chaperone Network in Plasmodium falciparum: Implications for Microtubule Homeostasis and Antimalarial Targeting

Abstract

Microtubules constitute fundamental cytoskeletal polymers that orchestrate cell division, intracellular trafficking, and the maintenance of cellular architecture across eukaryotic lineages. The biogenesis, folding, and steady-state homeostasis of αβ-tubulin heterodimers are tightly regulated by an evolutionarily conserved cohort of dedicated molecular chaperones, designated tubulin-specific chaperones (TBCs; TBCA–TBCE), acting in concert with the small GTPase Arl2. While this intricate assembly pathway has been extensively dissected in mammalian and plant systems, its existence, molecular architecture, and physiological relevance within the malaria parasite Plasmodium falciparum have remained entirely uncharted. In the present study, we undertake a rigorous, multi-layered in silico interrogation of the P. falciparum genome to identify and functionally contextualize the parasite’s putative tubulin-specific chaperones (PfTBCs). Through integrated sequence homology analyses, domain architecture mapping, and phylogenetic reconstruction, we establish the presence of clear orthologs corresponding to the canonical TBC repertoire. Subsequent functional annotation, coupled with protein-protein interaction network predictions, strongly implicates the role of PfTBCs in the coordinated assembly of αβ-tubulin heterodimers and the broader regulation of microtubule dynamics. Given the indispensable contribution of microtubule dynamics to parasite growth, asexual replication, gametocytogenesis, motility, and host-cell invasion, the identification of a conserved tubulin-folding machinery represents a significant conceptual advance. This work furnishes the first systematic evidence for an intact TBC-Arl2 pathway in P. falciparum, thereby laying a robust computational foundation for targeted experimental validation. Moreover, by highlighting PfTBCs as potentially essential and selectively vulnerable components of parasite cytoskeletal homeostasis, the study nominates these proteins as promising candidates for future antimalarial intervention strategies.