Atomic models possessing the common structural features identified for the cytochrome b(561) (cyt b(561)) protein family are presented. A detailed and extensive sequence analysis was performed in order to identify and characterize protein sequences in this family of transmembrane electron transport proteins. According to transmembrane helix predictions, all sequences contain 6 transmembrane helices of which 2-6 are located closely in the same regions of the 26 sequences in the alignment. A mammalian ( Homo sapiens) and a plant ( Arabidopsis thaliana) sequence were selected to build 3-dimensional structures at atomic detail using molecular modeling tools. The main structural constraints included the 2 pairs of heme-ligating His residues that are fully conserved in the family and the lipid-facing sides of the helices, which were also very well conserved. The current paper proposes 3-dimensional structures which to our knowledge are the first ones for any protein in the cyt b(561) family. The highly conserved His residues anchoring the two hemes on the cytoplasmic side and noncytoplasmic side of the membrane are in all proteins located in the transmembrane helices 2, 4 and 3, 5, respectively. Several highly conserved amino acids with aromatic side chain are identified between the two heme ligation sites. These residues may constitute a putative transmembrane electron transport pathway. The present study demonstrates that the structural features in the cyt b(561) family are well conserved at both the sequence and the protein level. The central 4-helix core represents a transmembrane electron transfer architecture that is highly conserved in eukaryotic species.
A central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here we used Rab10+/-mice to investigate the molecular mechanisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegeneration showed that Rab10+/-mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared to their Rab10+/+littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs) including Stx2, Stx1b, Vegfa, Lrrc25 (downregulated); and Prkaa2, Syt4 and Grin2d (upregulated). Behavioral testing showed that Rab10+/-mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace eyeblink conditioning, TECC) was significantly impaired. Therefore, our findings indicate that Rab10 differentially controls the brain circuitry of hippocampal-dependent spatial memory and higher-order behavior that requires intact cortex-hippocampal circuitry. Transcriptome and biochemical characterization of these mice suggest that glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D or GluN2D) is affected by Rab10 signaling. Further work is needed to evaluate whether GRIN2D mediates the behavioral phenotypes of the Rab10+/-mice. We conclude that Rab10+/-mice described here can be a valuable tool to study the mechanisms of resilience in Alzheimer’s disease model mice and to identify novel therapeutical targets to prevent cognitive decline associated with normal and pathological aging.SIGNIFICANCE STATEMENTAlzheimer’s disease (AD) is characterized by a widespread collapse of neuronal circuits that precedes amyloid plaque deposition and tau pathology. Yet, 30-50% of older individuals, who harbor the anatomical and molecular features of AD, preserve their cognitive abilities, and do not show AD symptoms in their lifetime. It has been suggested that the Rab10 protein is among the mediators of “cognitive resilience” against AD. The focus of this work was to characterize Rab10+/-mice behaviorally and molecularly, and to identify downstream targets of Rab10-dependent neuroresilience. The Rab10+/-mice described here can be used to study cellular and molecular mechanisms of Rab10-dependent resilience in mouse models of AD.
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