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Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants.

Gorman PM, Kim S, Guo M, Melnyk RA, McLaurin J, Fraser PE, Bowie JU, Chakrabartty A - BMC Neurosci (2008)

Bottom Line: We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients.We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada. pgorman@westwindpartners.ca

ABSTRACT

Background: Amyloid precursor protein (APP) is enzymatically cleaved by gamma-secretase to form two peptide products, either Abeta40 or the more neurotoxic Abeta42. The Abeta42/40 ratio is increased in many cases of familial Alzheimer's disease (FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains.

Results: Using synthetic peptides derived from the APP-TM domain, we show that this segment is capable of forming stable transmembrane dimers. A model of a dimeric APP-TM domain reveals a putative dimerization interface, and interestingly, majority of FAD mutations in APP are localized to this interface region. We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.

Conclusion: The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.

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Related in: MedlinePlus

Model of Alzheimer precursor protein transmembrane (APP-TM) dimer. The solid state NMR structure of the glycophorin A (GpA-TM) dimer, residues 75–87 (left), and the predicted APP-TM dimer, residue 705–717 (right) are compared. GpA-TM dimer contains the central G79VXXGV84 residues as the packing contacts, whereas APP-TM dimer packing utilizes G709VXXAT714 residues. Sequence alignment of APP-TM and GpA-TM (bottom) shows that residues comprising the packing interface are comparable in both sequences and denoted by capital letters. Exposed residues are shown as lowercase letters.
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Figure 3: Model of Alzheimer precursor protein transmembrane (APP-TM) dimer. The solid state NMR structure of the glycophorin A (GpA-TM) dimer, residues 75–87 (left), and the predicted APP-TM dimer, residue 705–717 (right) are compared. GpA-TM dimer contains the central G79VXXGV84 residues as the packing contacts, whereas APP-TM dimer packing utilizes G709VXXAT714 residues. Sequence alignment of APP-TM and GpA-TM (bottom) shows that residues comprising the packing interface are comparable in both sequences and denoted by capital letters. Exposed residues are shown as lowercase letters.

Mentions: We predicted a model for the APP-TM dimer structure using a previously described method that has proven to be remarkably accurate for modeling homo-oligomeric TM domains [6]. The predicted structure displays many similarities with the NMR structure of glycophorin A (GpA) [7] (Fig. 3). The GpA-TM dimer packing interface utilizes the sequence G79VXXGV84, while APP-TM dimer packing utilizes G709VXXAT714. Sequence alignment of APP-TM and GpA-TM (Fig. 3) shows that residues at the dimer interface are comparable in both sequences. A notable feature of the APP-TM model is that majority of the FAD mutations in the APP-TM domain are located within the predicted dimer interface (Table 1).


Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants.

Gorman PM, Kim S, Guo M, Melnyk RA, McLaurin J, Fraser PE, Bowie JU, Chakrabartty A - BMC Neurosci (2008)

Model of Alzheimer precursor protein transmembrane (APP-TM) dimer. The solid state NMR structure of the glycophorin A (GpA-TM) dimer, residues 75–87 (left), and the predicted APP-TM dimer, residue 705–717 (right) are compared. GpA-TM dimer contains the central G79VXXGV84 residues as the packing contacts, whereas APP-TM dimer packing utilizes G709VXXAT714 residues. Sequence alignment of APP-TM and GpA-TM (bottom) shows that residues comprising the packing interface are comparable in both sequences and denoted by capital letters. Exposed residues are shown as lowercase letters.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2266763&req=5

Figure 3: Model of Alzheimer precursor protein transmembrane (APP-TM) dimer. The solid state NMR structure of the glycophorin A (GpA-TM) dimer, residues 75–87 (left), and the predicted APP-TM dimer, residue 705–717 (right) are compared. GpA-TM dimer contains the central G79VXXGV84 residues as the packing contacts, whereas APP-TM dimer packing utilizes G709VXXAT714 residues. Sequence alignment of APP-TM and GpA-TM (bottom) shows that residues comprising the packing interface are comparable in both sequences and denoted by capital letters. Exposed residues are shown as lowercase letters.
Mentions: We predicted a model for the APP-TM dimer structure using a previously described method that has proven to be remarkably accurate for modeling homo-oligomeric TM domains [6]. The predicted structure displays many similarities with the NMR structure of glycophorin A (GpA) [7] (Fig. 3). The GpA-TM dimer packing interface utilizes the sequence G79VXXGV84, while APP-TM dimer packing utilizes G709VXXAT714. Sequence alignment of APP-TM and GpA-TM (Fig. 3) shows that residues at the dimer interface are comparable in both sequences. A notable feature of the APP-TM model is that majority of the FAD mutations in the APP-TM domain are located within the predicted dimer interface (Table 1).

Bottom Line: We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients.We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada. pgorman@westwindpartners.ca

ABSTRACT

Background: Amyloid precursor protein (APP) is enzymatically cleaved by gamma-secretase to form two peptide products, either Abeta40 or the more neurotoxic Abeta42. The Abeta42/40 ratio is increased in many cases of familial Alzheimer's disease (FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains.

Results: Using synthetic peptides derived from the APP-TM domain, we show that this segment is capable of forming stable transmembrane dimers. A model of a dimeric APP-TM domain reveals a putative dimerization interface, and interestingly, majority of FAD mutations in APP are localized to this interface region. We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.

Conclusion: The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.

Show MeSH
Related in: MedlinePlus