Microtubule-Actin Crosslinking Factor 1 and Plakins as Therapeutic Drug Targets.

Quincy Quick

doi:10.3390/ijms19020368

Abstract

Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin, envoplakin, periplakin, plectin, epiplakin) that network the three major filaments that comprise the cytoskeleton. Plakins have been found to be involved in disorders and diseases of the skin, heart, nervous system, and cancer that are attributed to autoimmune responses and genetic alterations of these macromolecules. Despite their role and involvement across a spectrum of several diseases, there are no current drugs or pharmacological agents that specifically target the members of this protein family. On the contrary, microtubules have traditionally been targeted by microtubule inhibiting agents, used for the treatment of diseases such as cancer, in spite of the deleterious toxicities associated with their clinical utility. The Research Collaboratory for Structural Bioinformatics (RCSB) was used here to identify therapeutic drugs targeting the plakin proteins, particularly the spectraplakins MACF1 and BPAG1, which contain microtubule-binding domains. RCSB analysis revealed that plakin proteins had 329 ligands, of which more than 50% were MACF1 and BPAG1 ligands and 10 were documented, clinically or experimentally, to have several therapeutic applications as anticancer, anti-inflammatory, and antibiotic agents.

Highlights

Mammalian plakins are a family of seven cytoskeletal proteins that were collectively identified and discovered between the early 80s and mid-90s [1,2,3,4,5,6,7]
MACF1 and BPAG1 perform crosslinking functions between actin and microtubules, while plectin crosslinks intermediate filaments to microtubules, and desmoplakin, envoplakin, periplakin, and epiplakin are predominately involved in intermediate filament binding as components of desmosomes and the cornified envelope
Little is known regarding the role of periplakin and envoplakin in human diseases and skin disorders, these plakins have been implicated in paraneoplastic pemphigus as a consequence of an autoimmune response to these proteins, like that observed for BPAG1 and desmoplakin in the related diseases [53,54]

Summary

Introduction

Mammalian plakins are a family of seven cytoskeletal proteins (microtubule-actin crosslinking factor 1-MACF1, bullous pemphigoid antigen 1-BPAG1, plectin, desmoplakin, envoplakin, periplakin, and epiplakin) that were collectively identified and discovered between the early 80s and mid-90s [1,2,3,4,5,6,7]. Despite their discovery over thirty years ago, much still remains to be determined regarding the biological function of plakins. Neuromuscular disease, Parkinson’s disease, cancer paraneoplastic pemphigus, pemphigus foliaceus, erythema multiforme, mucosal-dominant pemphigus vulgaris, multiple sclerosis, dystonia musculorum paraneoplastic pemphigus, pemphigus foliaceus, erythema multiforme, mucosal-dominant pemphigus vulgaris, cardiomyopathy, cancer paraneoplastic pemphigus paraneoplastic pemphigus, cancer epidermolysis bullosa simplex, cancer

Plakins and Disease

Cancer and Plakins

Microtubule-Targeted Drug Therapy

Findings

Therapeutic Targeting of Plakins