LIG_PROFILIN_1

Profilin (PF00235) is an abundant predominantly cytosolic protein that possesses an actin-binding activity (7758455;Ferron,2007) whereby it regulates the actin cytoskeleton; therefore, it is involved in many different biological processes ranging from cadherin binding (7758455) to actin-based mobility of pathogenic Listeria (9204886). In Homo sapiens there are two genes on chromosome 17, named PFN1 and PFN2, that code for two proteins (P07737 and P35080) having the same function even though the protein sequence is slightly different, as noted by the isoelectric point (pI) shows (pI (P07737 = 8.4; pI P35080 = 5.9)(7758455). The surface of profilins has two grooves, one required for actin binding and the other for binding proline-rich peptides (2PAV; 2V8C).
Actin polymerization is the process responsible for the formation of microfilaments. Each microfilament consists of a number of actin polymers plus other accessory proteins. Microfilaments are required for different functions from endocytosis/exocytosis to muscular contraction.
Several properties allow profilin to be a key regulator of the actin polymerization process. In particular, at high concentrations, it maintains actin in an unpolymerized status while it enhances the aforementioned process at low concentration (7758455); it binds different cytoskeletal proteins such as Ena/VASP (Kursula,2008) or Arp2/3. Profilin’s role in actin filament regulation is always undertaken cooperatively with sets of other proteins. The first step is called ‘actin nucleation’ and it sees the formation of an actin core initiated with three actin monomers from which a new actin filament will elongate. Among proteins that initiate nucleus formation, a major role is played by formins, a family of proteins that have a strong conserved C-terminal Formin Homology-2 (FH2) domain with an upstream formin homology-1 (FH1) domain. FH1 contains the Pro-rich profilin-binding motifs while FH2 interacts with monomers of globular actin (G-actin) and initiates nucleation. Higashida et al. (15044801) reported that mDia1, a member of the formin family, accelerates the actin nucleation rate and it associates with the barbed end of growing actin filament.
Enabled/Vasodilator-stimulated phosphoprotein (Ena/VASP) is another major protein in filament elongation requiring preformed F-actin to initiate further elongation. Ena/VASP contains different domains: N-terminal EVH1 domains, a Pro-rich domain and a C-terminal EVH2 domain (Siton-Mendelson,2017). Furthermore, the proline-rich domain could be split into three subdomains: a regulatory site, a recruiting domain which includes multiple repeats of the GPPPPP sequence and a “loading poly-Pro site”, which is required to deliver the profilin-actin complex from the poly-Pro region to the globular-actin-binding domain (GAB) of VASP (Ferron,2007). The proline-rich domain is responsible for the profilin-VASP interaction (Kursula,2008). The ability of VASP to promote actin filament elongation depends on its capability to recruit G-actin monomers and include them in the newly synthesized filament.
Profilin regulation of actin cytoskeletal organization is also involved in neurulation and commissure formation. Axonal growth responds to multiple cues present in the extracellular environment and this response triggers a signaling response which affect the cytoskeletal structures (26783725). Mammalian enabled (Mena) is a VASP family protein thought to be the linker between the signaling input and actin cytoskeleton remodelling. It is reported that Mena interacts with profilin thanks to a proline-rich segment (10069337) and Mena-deficient mice show abnormalities in the brain and die in utero.
Profilin interactions were also reported in Insects (Manseau,1996) and Fungi (Chang,1997;Evangelista,1997). In Drosophila, CAPPUCCINO (Q24120) interacts with profilin during embryonic development (Manseau,1996); in Saccharomyces cerevisiae Bni1pa yeast formin, associates with profilin and in Schizosaccharomyces pombe the complex cdc12p-profilin plays a key role during cell division (Mahoney,1997). All these proteins have Pro-rich motifs but the profilin interactions were only tested at whole protein level.
Intracellular pathogens need to control the actin cytoskeleton and several bacterial effector proteins are known to contain short motifs involved in actin filament regulation. Although no bacterial profilin-binding motif has been reported yet, several bacterial proteins functionally mimic profilin-interacting proteins to infect the host cells: for instance the organisms Burkholderia pseudomallei, Listeriamonocytogenes and Rickettsia (Siton-Mendelson,2017). The BimA effector of Burkholderia seems to mimic the function of VASP as it is also capable of nucleating actin (Benanti,2015) and has a long poly-Proline sequence thought likely to bind profilin. Bacteria from the genus Listeria use actin filaments as a sort of trail to move into the cell they have infected (9204886). The entire process requires ActA, a bacterial protein that is exposed on the cell surface, and cellular VASP, which interacts with ActA, and, in turn, tethers profilin to promote actin polymerization.