Protein structural and mechanistic basis of progeroid laminopathies

Abstract

Progeroid laminopathies are characterized by the premature appearance of certain signs of physiological aging in a subset of tissues. They are caused by mutations in genes coding for A-type lamins or lamin-binding proteins. Here, we review how different mutations causing progeroid laminopathies alter protein structure or protein-protein interactions and how these impact on mechanisms that protect cell viability and function. One group of progeroid laminopathies, which includes Hutchinson-Gilford progeria syndrome, is characterized by accumulation of unprocessed prelamin A or variants. These are caused by mutations in the A-type lamin gene (LMNA), altering prelamin A itself, or in ZMPSTE24, encoding an endoprotease involved in its processing. The abnormally expressed farnesylated proteins impact on various cellular processes that may contribute to progeroid phenotypes. Other LMNA mutations lead to the production of nonfarnesylated A-type lamin variants with amino acid substitutions in solventexposed hot spots located mainly in coil 1B and the immunoglobulin fold domain. Dominant missense mutations might reinforce interactions between lamin domains, thus giving rise to excessively stabilized filament networks. Recessive missense mutations in A-type lamins and barrier-toautointegration factor (BAF) causing progeroid disorders are found at the interface between these interacting proteins. The amino acid changes decrease the binding affinity of A-type lamins for BAF, which may contribute to lamina disorganization, as well as defective repair of mechanically induced nuclear envelope rupture. Targeting these molecular alterations in A-type lamins and associated proteins identified through structural biology studies could facilitate the design of therapeutic strategies to treat patients with rare but severe progeroid laminopathies.

Di-phosphorylated BAF shows altered structural dynamics and binding to DNA, but interacts with its nuclear envelope partners

“…Barrier-to-autointegration factor, encoded by the BANF1 gene and here referred as BAF, is an abundant and ubiquitously expressed DNA binding protein with multiple functions important for maintaining the integrity of the cellular genome ( 1–3 ). BAF A12T variant causes Nestor-Guillermo Progeria Syndrome (NGPS), a premature aging condition with early onset ( 4 , 5 ). BAF is highly conserved among metazoans, and BAF depletion is lethal during embryogenesis in Caenorhabditis elegans and Drosophila melanogaster ( 6–8 ).…”

Nucleoplasmic Lamin C Rapidly Accumulates at Sites of Nuclear Envelope Rupture with BAF and cGAS

“…We also show that LC accumulation at rupture sites depends on BAF, supporting the idea that LA/C and p-BAF form diffusible complexes in the nucleus. Recent studies have shown that phosphorylation of both Ser-4 and Thr-3 in BAF by the vaccinia-related kinase 1 (VRK1) greatly reduces the extensive flexibility of the N-terminal helix α1 and loop α1α2 to decrease the affinity for dsDNA but not the Ig-fold domain of LA/C (Marcelot et al, 2021;Nichols et al, 2006;Samson et al, 2018). Therefore, p-BAF in the nucleus might interact transiently with nuclear DNA (Shimi et al, 2004), such that the LA/C-p-BAF complex can freely diffuse throughout the nucleus.…”

Cell and Cell-Free Therapies to Counteract Human Premature and Physiological Aging: MSCs Come to Light

“…At the cellular level, laminopathies are characterized by alterations in the nuclear lamina, a mesh of intermediate filaments—A- and B-type lamins—that form a mesh lining the inner surface of the nuclear envelope [ 18 ]. Progeroid laminopathies originate by way of mutations in genes coding for A-type lamins ( LMNA ), their binding proteins ( BANF1, LEMD2 ) or in proteins that process A-type lamins ( ZMPSTE24 ) [ 19 ].…”