Giant scaffolding protein AHNAK1 interacts with β‐dystroglycan and controls motility and mechanical properties of schwann cells

Abstract

The profound morphofunctional changes that Schwann cells (SCs) undergo during their migration and elongation on axons, as well as during axon sorting, ensheathment, and myelination, require their close interaction with the surrounding laminin-rich basal lamina. In contrast to myelinating central nervous system glia, SCs strongly and constitutively express the giant scaffolding protein AHNAK1, localized essentially underneath the outer, abaxonal plasma membrane. Using electron microscopy, we show here that in the sciatic nerve of ahnak1(-) (/) (-) mice the ultrastructure of myelinated, and unmyelinated (Remak) fibers is affected. The major SC laminin receptor β-dystroglycan co-immunoprecipitates with AHNAK1 shows reduced expression in ahnak1(-) (/) (-) SCs, and is no longer detectable in Cajal bands on myelinated fibers in ahnak1(-) (/) (-) sciatic nerve. Reduced migration velocity in a scratch wound assay of purified ahnak1(-) (/) (-) primary SCs cultured on a laminin substrate indicated a function of AHNAK1 in SC motility. This was corroborated by atomic force microscopy measurements, which revealed a greater mechanical rigidity of shaft and leading tip of ahnak1(-) (/) (-) SC processes. Internodal lengths of large fibers are decreased in ahnak1(-) (/) (-) sciatic nerve, and longitudinal extension of myelin segments is even more strongly reduced after acute knockdown of AHNAK1 in SCs of developing sciatic nerve. Together, our results suggest that by interfering in the cross-talk between the transmembrane form of the laminin receptor dystroglycan and F-actin, AHNAK1 influences the cytoskeleton organization of SCs, and thus plays a role in the regulation of their morphology and motility and lastly, the myelination process.

The MyMOMA domain of MYO19 encodes for distinct Miro-dependent and Miro-independent mechanisms of interaction with mitochondrial membranes

“…VDAC2 are mitochondrial outer membrane porins involved in ATP homeostasis [Colombini 2012;Saks et al 1995], and in some instances may be regulated by interaction with microtubules [Ramos et al 2019]. AHNAK is a large scaffolding protein with the ability to bind actin and other cellular components in a variety of cellular contexts [Davis et al 2014], including muscle contraction [Haase et al 2004], cancer [Shankar et al 2010], and Schwann cell function [von Boxberg et al 2014]. Filamins are actin crosslinking proteins involved in actin-based cellular activities via interactions with a large number of other protein partners [Nakamura et al 2011].…”

Unwrapping the unappreciated: recent progress in Remak Schwann cell biology

“…One Gpr126 binding partner, Laminin-211, has been repeatedly implicated in both myelinating SC and RSC biology [27,30] (reviewed in [2]). Additionally, the scaffold protein AHNAK1 was recently shown to bind the laminin receptor β-dystroglycan to facilitate communication between the SC basal lamina and the actin cytoskeleton to control SC motility and RSC ensheathment [31]. Together with studies of the Nrg1-III/ErbB and PI3K/mTOR signaling pathways, the effects of Gpr126 signaling clearly illustrate that, currently, most of the molecules known to impact RSCs also have strong roles in myelinating SCs.…”

The MyMOMA domain of MYO19 encodes for distinct Miro‐dependent and Miro‐independent mechanisms of interaction with mitochondrial membranes

“…Of those proteins, four were cross-listed in BIOGRID data for MYO19 interactors previously identified by affinity-capture mass spectrometry [Color figure can be viewed at wileyonlinelibrary.com] in some instances may be regulated by interaction with microtubules (Ramos, Hughes, & Perry, 2019). AHNAK is a large scaffolding protein with the ability to bind actin and other cellular components in a variety of cellular contexts (Davis, Loos, & Engelbrecht, 2014), including muscle contraction (Haase et al, 2004), cancer (Shankar et al, 2010), and Schwann cell function (von Boxberg et al, 2014). Filamins are actin crosslinking proteins involved in actin-based cellular activities via interactions with a large number of other protein partners (Nakamura, Stossel, & Hartwig, 2011).…”