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

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.

Keywords: bullous pemhigoid; cancer; cardiomyopathy; drug targets; plakins.

Figure 1

Domain regions and organizational structure of plakin proteins. CH-ABD: calponin homology actin-binding domain; SR: spectrin repeats; EFH: EF-hand calcium-binding domain; GAS2-MTBD—growth-arrest specific protein 2 microtubule binding domain; Plec: plectin; SBCC: DNA repair exonuclease SbcCD ATPase subunit domain; PD: Plectin domain; Cast: RIM-binding protein of the cytomatrix active zone; Smc: Chromosome segregation ATPase; SCP: Synaptonemal complex protein 1.

Figure 2

Plakin proteins participate in intracellular signaling cascades. (A) MACF1–Wnt signaling (dashed arrow: WNT signaling mediators interacting with WNT receptor), (B) Plectin–PKC–ERK signaling (solid red line: intact plectin; dashed red line: inhibited down-regulated plectin).

Figure 3

Ibrutinib (A) and tacrolimus (B) drug ligands interacting with 3D ribbon structures of calcium-dependent protein kinase 1 and calcineurin A and B proteins, respectively, indexed in the Research Collaboratory for Structural Bioinformatics protein data bank (RSCB PDB). Images produced in the RSCB PDB [87]. Figure 3 and Figure 4 do not need copyright permission only to be cited as has been done.

Figure 4

4-[3-hydroxyanilino]-6,7-dimethoxyquinazoline (A) and PP121 (B) drug ligands interacting with the calcium-dependent protein kinase 1, 3D ribbon structure indexed in the RSCB PDB. Images produced in the RSCB PDB [87].

Figure 5

Putative binding sites of drug ligands with domains of spectraplakin proteins. CH/ABD:Calponin homology actin-binding domain; PD: plakin domain; PRD: plakin repeat domain; SR: spectrin repeat; EFH: EF-hand calcium-binding motif region; MTBD: microtubule-binding domain.

Figure 6

Plectin anticancer antibiotic ligands.

Figure 7

Targeted inhibition of plakin proteins impairs the crosslinking functions necessary for tumorigenic cell behaviors and responses.