Profilin1 biology and its mutation, actin(g) in disease

Abstract

Profilins were discovered in the 1970s and were extensively studied for their significant physiological roles. Profilin1 is the most prominent isoform and has drawn special attention due to its role in the cytoskeleton, cell signaling, and its link to conditions such as cancer and vascular hypertrophy. Recently, multiple mutations in the profilin1 gene were linked to amyotrophic lateral sclerosis (ALS). In this review, we will discuss the physiological and pathological roles of profilin1. We will further highlight the cytoskeletal function and dysfunction caused by profilin1 dysregulation. Finally, we will discuss the implications of mutant profilin1 in various diseases with an emphasis on its contribution to the pathogenesis of ALS.

Keywords: Actin-binding domain; Axonal dynamics; Motor neuron disease; Neurodegeneration; PFN1 aggregation; PFN1 instability; PFN1G118V; PLP domain; Polymerization.

Fig. 1

Profilin1 protein structure and ALS-linked mutations. a Schematic presentation of profilin1, including the five α-helices (tan) and seven β-sheets (green). Eight of the ALS-linked mutations are indicated by black arrows. Three amino acids residues with notable phosphorylation sites on the C-terminal are highlighted (S137 and Y129) and one is at position of T109 that is mutated in ALS. b Three-dimensional structure of human profilin1 (PDB: 1fik) in cartoon representation. The ALS-linked mutations are labeled. Crystal structure data of bovine profilin-1 were downloaded from protein data base (PDB) to show predicted human profilin1 3-D structure: 4X1L and ALS-linked mutation were added using PyMOL (The PyMol Molecular Graphics System, Version 1.5.0.4, Schrodinger, LLC)

Fig. 2

a Diagrammatic scheme depicting profilin1 regulation of actin polymerization. b Diagrammatic scheme depicting the events by which mutations in profilin1 disrupt actin polymerization, thereby potentially causing motor neuron degeneration

Fig. 3

a Schematic demonstration of profilin1 actin binding. Predicted structure of human profilin1 PDB: 4X1L (yellow) and β-actin PDB: 2BTF (green) complex based on a bovine structure (2BTF) represented in cartoon. The mutated profilin1 residues involved in ALS are colored and shown in space fill. All these images were generated using PyMOL. Residues in profilin1 that makes contact with beta actin [7] are shown in cyan in dots on the top of actin (shown in green). b Crystal structure of human profilin-1 showing ALS-linked mutations. Three-dimensional structure of profilin1 was downloaded from PDB: 4X1L and mutated using PyMOL. Actin-binding domain is shown in cyan in dots

Fig. 4

Diseases caused by dysregulation or mutations of profilin1