Title

Designing a PDZ Chelator for Alzheimer's Peptides Based on the Knob-Socket Model

Poster Number

17A

Lead Author Major

Biological Sciences, Pre-dentistry 3+3

Lead Author Status

Junior

Second Author Major

Biological Sciences, Pre-dentistry 3+3

Second Author Status

Junior

Third Author Major

Biochemistry

Third Author Status

Junior

Format

Poster Presentation (Research Day, April 30)

Faculty Mentor Name

Jerry Tsai

Faculty Mentor Department

Chemistry

Additional Faculty Mentor Name

Hyun Joo

Additional Faculty Mentor Department

Chemistry

Abstract/Artist Statement

PDZ domains bind to the C-terminal peptide of other proteins with affinities ranging from mM to high nM. Understanding the basis for peptide specificity to PDZ domains could open possibilities to change the PDZ domain into a chelator of peptides and treatment for Alzheimer’s disease. The Knob-Socket model was used to identify the amino acid residues critical for the affinity and specificity to PDZ domains. The PDZ domain structure comprises 5 β-strands and 2 α-helices connected by 6 coil/turn segments. Analyses of 85 PDZ domains uncover a canonical set of interactions with residues in the peptides that determine binding pocket specificity. For consistency with previous works, the peptide positions are numbered backward from P0 at the C-terminal position with negative numbering towards the N-terminus. The P0 residue position packs into sockets formed by the second coil residues in the S0 pocket and into sockets in the longer second α-helix(H2). The P-2 residue also often packs into H2 in conjunction with the P0 residue. Markedly, the peptide extends the β-sheet of PDZ domains as a 6th strand in such a way that the peptide interacts closely with the neighboring β-strands. With this canonical model of peptide binding, the specificity of PDZ domains towards a peptide can be adjusted to bind amyloid-β(Aβ) peptides: (1) P0 residue should pack into sockets in both coil and H2, (2) peptide should extend the β-sheet by binding S2, (3) peptide residue should pack into the hairpin coil connecting S2 and S3. Based on these findings, a PDZ domain can become an effective chelator of Aβ-peptides. Aβ42 is such an example peptide, containing P0/Ala, P-1/Ile, and P-2/Val. A PDZ chelator for Aβ42 should bind with an affinity close to those of known peptides binding PDZ domains.

Location

Information Commons, William Knox Holt Memorial Library and Learning Center

Start Date

30-4-2022 1:00 PM

End Date

30-4-2022 3:00 PM

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Apr 30th, 1:00 PM Apr 30th, 3:00 PM

Designing a PDZ Chelator for Alzheimer's Peptides Based on the Knob-Socket Model

Information Commons, William Knox Holt Memorial Library and Learning Center

PDZ domains bind to the C-terminal peptide of other proteins with affinities ranging from mM to high nM. Understanding the basis for peptide specificity to PDZ domains could open possibilities to change the PDZ domain into a chelator of peptides and treatment for Alzheimer’s disease. The Knob-Socket model was used to identify the amino acid residues critical for the affinity and specificity to PDZ domains. The PDZ domain structure comprises 5 β-strands and 2 α-helices connected by 6 coil/turn segments. Analyses of 85 PDZ domains uncover a canonical set of interactions with residues in the peptides that determine binding pocket specificity. For consistency with previous works, the peptide positions are numbered backward from P0 at the C-terminal position with negative numbering towards the N-terminus. The P0 residue position packs into sockets formed by the second coil residues in the S0 pocket and into sockets in the longer second α-helix(H2). The P-2 residue also often packs into H2 in conjunction with the P0 residue. Markedly, the peptide extends the β-sheet of PDZ domains as a 6th strand in such a way that the peptide interacts closely with the neighboring β-strands. With this canonical model of peptide binding, the specificity of PDZ domains towards a peptide can be adjusted to bind amyloid-β(Aβ) peptides: (1) P0 residue should pack into sockets in both coil and H2, (2) peptide should extend the β-sheet by binding S2, (3) peptide residue should pack into the hairpin coil connecting S2 and S3. Based on these findings, a PDZ domain can become an effective chelator of Aβ-peptides. Aβ42 is such an example peptide, containing P0/Ala, P-1/Ile, and P-2/Val. A PDZ chelator for Aβ42 should bind with an affinity close to those of known peptides binding PDZ domains.