The Amyloid Precursor Protein Has a Flexible Transmembrane Domain and Binds Cholesterol

Barrett, Paul J.; Song, Yuanli; Horn, Wade D. Van; Hustedt, Eric J.; Schafer, Johanna M.; Hadziselimovic, Arina; Beel, Andrew J.; Sanders, Charles R.

doi:10.1126/science.1219988

Cited by 445 publications

(918 citation statements)

References 43 publications

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“…1b). Sequence analysis identified a conserved glycine zipper motif GxxxGxxxG, known to promote homo-oligomerization 16,17 , located in the third predicted transmembrane region. Disulphide bonds were predicted using DIpro 18 (http://scratch.proteomics.ics.uci.edu), which would promote stabilization of the dimer.…”

Section: Resultsmentioning

confidence: 99%

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

et al. 2015

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Membrane proteins are crucial to heart function and development. Here we combine cationic silica-bead coating with shotgun proteomics to enrich for and identify plasma membrane-associated proteins from primary mouse neonatal and human fetal ventricular cardiomyocytes. We identify Tmem65 as a cardiac-enriched, intercalated disc protein that increases during development in both mouse and human hearts. Functional analysis of Tmem65 both in vitro using lentiviral shRNA-mediated knockdown in mouse cardiomyocytes and in vivo using morpholino-based knockdown in zebrafish show marked alterations in gap junction function and cardiac morphology. Molecular analyses suggest that Tmem65 interaction with connexin 43 (Cx43) is required for correct localization of Cx43 to the intercalated disc, since Tmem65 deletion results in marked internalization of Cx43, a shorter half-life through increased degradation, and loss of Cx43 function. Our data demonstrate that the membrane protein Tmem65 is an intercalated disc protein that interacts with and functionally regulates ventricular Cx43.

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Section: Resultsmentioning

confidence: 99%

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

et al. 2015

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“…Intriguingly, Fspondin also modulates amyloid-β precursor protein (APP) cleavage by binding to the initial α/β-cleavage site of APP (11). APP has recently been found to bind to cholesterol (12), which makes up much of the myelin composition of white matter fibers. Additionally, many proteins and genes involved in APP processing, including F-spondin (SPON1), also interact with the family of receptors for apolipoprotein E, which is coded for by the gene APOE-a robust Alzheimer's disease (AD) genetic risk factor (13,14).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide scan of healthy human connectome discoversSPON1gene variant influencing dementia severity

Jahanshad

Rajagopalan

Hou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

147

128

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Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, highangular resolution diffusion MRI. We adapted GWASs to screen the brain's connectivity pattern, allowing us to discover genetic variants that affect the human brain's wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer's disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.diffusion tensor imaging | neuroimaging genetics | graph theory | HARDI tractography | multiple comparisons correction H uman brain anatomy involves a complex network of structural and functional pathways that connect anatomically distinct regions. These pathways can be visualized, on a gross anatomical scale, with diffusion imaging-based tractography (1). Neural pathways change as our brains develop (2, 3) and are altered in neurodegenerative conditions, including Alzheimer's disease (4). Our individual genetic makeup exerts a strong influence on the functional synchronization of brain regions (5) and the patterning of cortical structure (6, 7), but particular genes that impact the brain's neural connectivity are still largely unknown.To empower the search for genes that affect the brain's connectivity patterns, we first studied a large twin and family cohort consisting of 366 young adults (ages 20-29 y) from 223 families. We used anatomical brain MRI combined with high-angular resolution diffusion imaging (HARDI) at high magnetic field (4 T) to subdivide cortical regions into areas of known structure and function (8), while also mapping the white matter fiber pathways between them with high-resolution tractography. We defined connectivity maps...

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“…This is in accordance with ample space in the S2P open conformation to accommodate the substrate in an α-helical (rather than extended) conformation. A similar picture has been obtained for APP, in which a flexible, bent TM domain might serve to most effectively interact with the protease (29). The TM region C-terminal to the hinge, however, is characterized by its more ambiguous hydropathy properties and the connection to the NP motif on one side and the highly mobile linker on the other.…”

Section: Discussionmentioning

confidence: 69%

“…Currently, it is largely unclear what makes a substrate suitable or unsuitable for RIP and how the lipid environment within the membrane space impinges on these properties (26,27). For example, γ-secretase, involved in cleavage of the APP and the Notch receptor, has a large number of different substrates, for which only a loose definition of common features can be given (28,29). In rhomboids, the membrane-integral serine protease relatives of S2Ps, which regulate epidermal growth factor receptor (EGFR) signaling in Drosophila (17,30), common features for substrate recognition (31,32) have long been elusive.…”

mentioning

confidence: 99%

The membrane anchor of the transcriptional activator SREBP is characterized by intrinsic conformational flexibility

Linser

Salvi

Briones

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Regulated intramembrane proteolysis (RIP) is a conserved mechanism crucial for numerous cellular processes, including signaling, transcriptional regulation, axon guidance, cell adhesion, cellular stress responses, and transmembrane protein fragment degradation. Importantly, it is relevant in various diseases including Alzheimer's disease, cardiovascular diseases, and cancers. Even though a number of structures of different intramembrane proteases have been solved recently, fundamental questions concerning mechanistic underpinnings of RIP and therapeutic interventions remain. In particular, this includes substrate recognition, what properties render a given substrate amenable for RIP, and how the lipid environment affects the substrate cleavage. Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors are critical regulators of genes involved in cholesterol/lipid homeostasis. After site-1 protease cleavage of the inactive SREBP transmembrane precursor protein, RIP of the anchor intermediate by site-2 protease generates the mature transcription factor. In this work, we have investigated the labile anchor intermediate of SREBP-1 using NMR spectroscopy. Surprisingly, NMR chemical shifts, site-resolved solvent exposure, and relaxation studies show that the cleavage site of the lipid-signaling protein intermediate bears rigid α-helical topology. An evolutionary conserved motif, by contrast, interrupts the secondary structure ∼9-10 residues C-terminal of the scissile bond and acts as an inducer of conformational flexibility within the carboxyl-terminal transmembrane region. These results are consistent with molecular dynamics simulations. Topology, stability, and site-resolved dynamics data suggest that the cleavage of the α-helical substrate in the case of RIP may be associated with a hinge motion triggered by the molecular environment.SREBP | regulated intramembrane proteolysis | membrane proteins | cellular lipid homeostasis | cancer

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The Amyloid Precursor Protein Has a Flexible Transmembrane Domain and Binds Cholesterol

Cited by 445 publications

References 43 publications

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

Genome-wide scan of healthy human connectome discoversSPON1gene variant influencing dementia severity

The membrane anchor of the transcriptional activator SREBP is characterized by intrinsic conformational flexibility

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