Myosin Va and spermine synthase: partners in exosome transport

Abstract

A recent paper in Bioscience Reports (BSR20182189) describes the discovery of an interaction between the motor protein myosin Va and the metabolic enzyme spermine synthase. Myosin Va is a molecular motor which plays a key role in vesicle transport. Mutations in the gene which encodes this protein are associated with Griscelli syndrome type 1 and the 'dilute' phenotype in animals. Spermine synthase catalyzes the conversion of spermidine to spermine. This largely cytoplasmic enzyme can also be localized to the soluble fraction in exosomes. Mutations in the spermine synthase gene are associated with Snyder Robinson mental retardation syndrome. The interaction between the two proteins was detected using the yeast two hybrid method and verified by microscale thermophoresis of recombinant proteins. Knockdown of the MYO5A gene reduced the expression of mRNA coding for spermine synthase. The amount of this transcript was also reduced in cells derived from a patient with Griscelli syndrome type 1. This suggests that, in addition to a direct physical interaction between the two proteins, myosin Va also modulates the transcription of the spermine synthase gene. The mechanism for this modulation is currently unknown. These findings have implications for Griscelli syndrome type 1 and Snyder Robinson mental retardation syndrome. They also suggest that interactions between myosin Va and soluble exosome proteins such as spermine synthase may be important in the mechanism of exosome transport.

Keywords: Griscelli syndrome; Snyder Robinson mental retardation syndrome; cytoskeleton; exosome transport; myosin superfamily; polyamine synthesis.

Figure 1. Structures of the proteins involved in this work

(A)(i) Myosin 5a in the lower activity inhibited state (PDB: 2DFS [10]). The globular, motor domains are shown toward the top of the image. These form the N-terminal domains of the two heavy chains (purple and orange). The heavy chain then extends into a largely α-helical structure, which bends round in a U-shape, forming a coiled-coil region with the other heavy chain toward the C-terminus. Six calmodulin molecules (various colors) can be seen wrapped around this U-shaped region of each heavy chain. This structure lacks the GTD which is responsible for binding to the various ‘cargoes’ which are transported by the motor. (ii) The GTD from human myosin Va (PDB: 4J5L [9]). (B) The reaction catalyzed by spermine synthase. This reaction converts spermidine (N¹-(3-aminopropyl)butane-1,4-diamine) to spermine (N¹,N⁴-bis(3-aminopropyl)butane-1,4-diamine) using decarboxylated S-adenosylmethionine (dcAdoMet) as the donor of the 1-aminopropylgroup. (C) The structure of the spermine synthase dimer (PDB: 3C6M [36]). The two subunits of the dimer are shown in red and blue, with the N-terminal domain at the top of the image. Substrates can be seen bound to the C-terminal domain. Protein images were generated using UCSF Chimera, version 1.10.2 [53].