Numerous mutations in each of the mitochondrial aminoacyl‐tRNA synthetases (aaRSs) have been implicated in human diseases. The mutations are autosomal and recessive and lead mainly to neurological disorders, although with pleiotropic effects. The processes and interactions that drive the etiology of the disorders associated with mitochondrial aaRSs (mt‐aaRSs) are far from understood. The complexity of the clinical, genetic, and structural data requires concerted, interdisciplinary efforts to understand the molecular biology of these disorders. Toward this goal, we designed MiSynPat, a comprehensive knowledge base together with an ergonomic Web server designed to organize and access all pertinent information (sequences, multiple sequence alignments, structures, disease descriptions, mutation characteristics, original literature) on the disease‐linked human mt‐aaRSs. With MiSynPat, a user can also evaluate the impact of a possible mutation on sequence‐conservation‐structure in order to foster the links between basic and clinical researchers and to facilitate future diagnosis. The proposed integrated view, coupled with research on disease‐related mt‐aaRSs, will help to reveal new functions for these enzymes and to open new vistas in the molecular biology of the cell. The purpose of MiSynPat, freely available at http://misynpat.org, is to constitute a reference and a converging resource for scientists and clinicians.

Cell adhesion molecule L1 regulates multiple cell functions and L1 deficiency is linked to several neural diseases. Proteolytic processing generates functionally decisive L1 fragments, which are imported into the nucleus. By computational analysis, we found at L1's C‐terminal end the chromo shadow domain‐binding motif PxVxL, which directs the binding of nuclear proteins to the heterochromatin protein 1 (HP1) isoforms α, β, and ɣ. By enzyme‐linked immunosorbent assay, we show that the intracellular L1 domain binds to all HP1 isoforms. These interactions involve the HP1 chromo shadow domain and are mediated via the sequence 1158KDET1161 in the intracellular domain of murine L1, but not by L1's C‐terminal PxVxL motif. Immunoprecipitation using nuclear extracts from the brain and from cultured cerebellar and cortical neurons indicates that HP1 isoforms interact with a yet unknown nuclear L1 fragment of approximately 55 kDa (L1‐55), which carries ubiquitin residues. Proximity ligation indicates a close association between L1‐55 and the HP1 isoforms in neuronal nuclei. This association is reduced after the treatment of neurons with inhibitors of metalloproteases, β‐site of amyloid precursor protein cleaving enzyme (BACE1), or ɣ‐secretase, suggesting that cleavage of full‐length L1 by these proteases generates L1‐55. Reduction of HP1α, ‐β, or ‐ɣ expression by siRNA decreases L1‐dependent neurite outgrowth from cultured cortical neurons and decreases the L1‐dependent migration of L1‐transfected HEK293 cells in a scratch assay. These findings indicate that the interaction of the novel fragment L1‐55 with HP1 isoforms in nuclei affects L1‐dependent functions, such as neurite outgrowth and neuronal migration.