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The mitochondrial outer membrane creates a diffusion barrier between the cytosol and mitochondrial intermembrane space, allowing the exchange of metabolic products, important for efficient mitochondrial function in neurons. The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial outer membrane protein with a critical role in mitochondrial dynamics and metabolic balance in neurons. Missense mutations in theGDAP1gene are linked to the most common human peripheral neuropathy, Charcot-Marie-Tooth disease (CMT). GDAP1 is a distant member of the glutathione-S-transferase (GST) superfamily, with unknown enzymatic properties or functions at the molecular level. The structure of the cytosol-facing GST-like domain has been described, but there is no consensus on how the protein interacts with the mitochondrial outer membrane. Here, we describe a model for GDAP1 assembly on the membrane using peptides vicinal to the GDAP1 transmembrane domain. We used oriented circular dichroism spectroscopy (OCD) with synchrotron radiation to study the secondary structure and orientation of GDAP1 segments at the outer and inner surfaces of the outer mitochondrial membrane. These experiments were complemented by small-angle X-ray scattering, providing the first experimental structural models for full-length human GDAP1. The results indicate that GDAP1 is bound into the membraneviaa single transmembrane helix, flanked by two peripheral helices interacting with the outer and inner leaflet of the mitochondrial outer membrane in different orientations. Impairment of such interactions could be a mechanism for CMT in the case of missense mutations affecting these segments instead of the GST-like domain.

Postglacial faults (PGFs) are common SW-NE-trending features in the northern part of the Fennoscandian shield being attributed to former high-magnitude (Mw ≈ 7–8.2) earthquakes (Arvidsson, 1996). These are of interest for the long-term seismic hazard of deep geological nuclear waste repositories. The PGFs are still seismically active; and many of the deformation features, such as paleolandslides, are spatially coextensive within these earthquake zones. Based on the 14C-datings of landslide-buried organic materials, three postglacial seismic episodes (≈9.7–11, ≈5–6, and 1.3–1.8 ky ago) have been found in western Finnish Lapland. Because the model predictions by Wu et al. (1999) suggested that the onset of fault instability started at 15 ky and that the maximum fault instability was reached at 13–10 ky in Fennoscandia, we postulate that not only subaerial but also subglacial types of deformations may have been associated with the past seismic events. Here, we present LiDAR DEM observations and sediment electromagnetic anisotropy data on the landforms, such as the rim-ridged/arcuate Pulju moraine (Kujansuu, 1967), roundish (liquefaction) bowls, postdepositional (liquefaction) deformations on streamlined landforms, as well as hummocky ridge fields of massflow sediments. The sediments in the Pulju moraine and massflow ridges displayed clear anisotropy, indicating lateral transportation in subglacial wet-based environment. Instead, sediments in the bowl-shaped morphologies next to PGFs and deformed ice-stream flutings tended to be isotropic, suggesting postdepositional and vertical liquefaction processes. Based on the LiDAR morphology and sedimentary anisotropy data, these landforms may be linked to past earthquakes.

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders. Despite the common involvement of ganglioside-induced differentiation-associated protein 1 (GDAP1) in CMT, the protein structure and function, as well as the pathogenic mechanisms, remain unclear. We determined the crystal structure of the complete human GDAP1 core domain, which shows a novel mode of dimerization within the glutathione S-transferase (GST) family. The long GDAP1-specific insertion forms an extended helix and a flexible loop. GDAP1 is catalytically inactive towards classical GST substrates. Through metabolite screening, we identified a ligand for GDAP1, the fatty acid hexadecanedioic acid, which is relevant for mitochondrial membrane permeability and Ca2+homeostasis. The fatty acid binds to a pocket next to a CMT-linked residue cluster, increases protein stability, and induces changes in protein conformation and oligomerization. The closest homologue of GDAP1, GDAP1L1, is monomeric in its full-length form. Our results highlight the uniqueness of GDAP1 within the GST family and point towards allosteric mechanisms in regulating GDAP1 oligomeric state and function.

The Vaalajarvi-Ristonmannikko glacially induced fault (GIF) system in central Finnish Lapland is attributed to multiple slip events (Mw ≈ 6.7–7.0 earthquakes), likely contributing to subglacial and postglacial sediment deformations. We applied light detection and ranging digital elevation models (LiDAR DEMs), electrical-sedimentary anisotropy (orientation) measurements and trenching to study the related geomorphology, particularly subglacial moraines on the hanging wall of the Ristonmannikko GIF segment striking SW-NE direction. Transverse-to-ice-flow-oriented moraines and the Pulju moraines were found to cover the distal tails of the Early Weichselian rock-drumlins and they are interpreted as seismically induced crevasse infill landforms. The electrical-sedimentary anisotropy suggests squeeze-up origin rather than active ice oscillation end moraine formation processes. Based on our recent OSL-data, the squeeze-up moraines are also superimposed on a till-covered esker system yielding an age of 87 ka. Erosional V-shaped features with apices pointing up-ice were found on convex surfaces of the distal rock-drumlin tails and were attributed to subglacial mass-flows rather than glaciofluvial erosion or frozen bed fracturing mechanisms. The area lacks glaciofluvial/hummocky corridors, but a substantial outburst system on the streak of Ristonmannikko GIF suggests an earthquake-triggered outburst of the former subglacial Lake Unari. Our recent 14C ages of paleolandslides suggest that the Vaalajarvi-Ristonmannikko GIF terrain was ice-free already 11.3 cal kyr BP, but was subjected to lithospheric water discharge and landslide events at 2.9 and 10.6 cal kyr BP. The squeeze-up moraines most likely formed during the later phase of the Younger Dryas, between ca. 12.0–11.5 cal kyr BP. We propose that subglacial seismicity within a glacial isostatic adjustment (GIA) environment was a notable trigger for the squeeze-up and mass-flow features beneath the retreating Fennoscandian Ice Sheet (FIS) during the later phase of the Younger Dryas.

The journal of biological chemistry 296, 100197 (2021). doi:10.1074/jbc.RA120.016542, Prolyl 4-hydroxylases (P4Hs) catalyze post-translational hydroxylation of peptidyl proline residues. In addition to collagen P4Hs and hypoxia-inducible factor P4Hs, a third P4H – the poorly characterized endoplasmic reticulum (ER)-localized transmembrane prolyl 4-hydroxylase (P4H-TM) – is found in animals. P4H-TM variants are associated with the familiar neurological HIDEA syndrome, but how these variants might contribute to disease is unknown. Here, we explored this question in a structural and functional analysis of soluble human P4H-TM. The crystal structure revealed an EF-domain with two Ca$^{2+}$-binding motifs inserted within the catalytic domain. A substrate-binding groove was formed between the EF-domain and the conserved core of the catalytic domain. The proximity of the EF-domain to the active site suggests that Ca$^{2+}$-binding is relevant to the catalytic activity. Functional analysis demonstrated that Ca$^{2+}$-binding affinity of P4H-TM is within the range of physiological Ca$^{2+}$ concentration in the ER. P4H-TM was found both as a monomer and a dimer in solution, but the monomer-dimer equilibrium was not regulated by Ca$^{2+}$. The catalytic site contained bound Fe$^{2+}$ and N-oxalylglycine, which is an analogue of the cosubstrate 2-oxoglutarate. Comparison to homologous P4H structures complexed with peptide substrates showed that the substrate interacting residues and the lid structure that folds over the substrate are conserved in P4H-TM, whereas the extensive loop structures that surround the substrate-binding groove, generating a negative surface potential, are different. Analysis of the structure suggests that the HIDEA variants cause loss of P4H-TM function. In conclusion, P4H-TM shares key structural elements with other P4Hs while having an unique EF-domain., Published by Soc., Bethesda, Md.