Ankyrin repeat

Ankyrin repeat

The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and "Drosophila" Notch. Ankyrin repeats mediate protein-protein interactions and are among the most common structural motifs in known proteins. They appear in bacterial, archaeal, and eukaryotic proteins, but are far more common in eukaryotes. Most proteins that contain the motif have four to six repeats, although its namesake ankyrin contains 24 and the largest known number of repeats is 34, predicted in a protein expressed by "Giardia lamblia".cite journal |author=Mosavi L, Cammett T, Desrosiers D, Peng Z |title=The ankyrin repeat as molecular architecture for protein recognition |journal=Protein Sci |volume=13 |issue=6 |pages=1435–48 |year=2004 |pmid=15152081 |url=http://www.proteinscience.org/cgi/content/full/13/6/1435 |doi=10.1110/ps.03554604]

The ankyrin-repeat sequence motif has been studied using multiple sequence alignment to determine which conserved amino acid residues are critical for folding and stability. The residues that appear on the wide lateral surface of ankyrin repeat structures are variable, often hydrophobic, and involved mainly in mediating protein-protein interactions. An artificial protein design based on a consensus sequence derived from sequence alignment has been synthesized and found to fold stably, representing the first designed protein with multiple identical repeats.Mosavi LK, Minor DL Jr, Peng ZY. (2002). Consensus-derived structural determinants of the ankyrin repeat motif. "Proc Natl Acad Sci USA" 99(25):16029-34. PMID 12461176 http://www.pnas.org/cgi/content/full/99/25/16029] More extensive design strategies have used combinatorial sequences to "evolve" ankyrin-repeat motifs that specifically recognize particular protein targets, a technique that has been presented as a possible alternative to antibody design for applications requiring high-affinity binding.Binz HK, Amstutz P, Kohl A, Stumpp MT, Briand C, Forrer P, Grutter MG, Pluckthun A. (2004). High-affinity binders selected from designed ankyrin repeat protein libraries. "Nat Biotechnol" 22(5):575-82. PMID 15097997 ]

Ankyrin-repeat proteins present an unusual problem in the study of protein folding, which has largely focused on globular proteins that form well-defined tertiary structure stabilized by long-range, nonlocal residue-residue contacts. Ankyrin repeats, by contrast, contain very few such contacts (that is, they have a low contact order). Most studies have found that ankyrin repeats fold in a two-state folding mechanism, suggesting a high degree of folding cooperativity despite the local inter-residue contacts and the evident need for successful folding with varying numbers of repeats. Some evidence, based on synthesis of truncated versions of natural repeat proteinsZhang B, Peng ZY. (2000). A minimum folding unit in the ankyrin repeat protein p16(INK4). "J Mol Biol" 299: 1121–1132 10843863] and on the examination of phi values,Tang KS, Fersht AR, Itzhaki LS (2003). Sequential unfolding of ankyrin repeats in tumor suppressor p16. "Structure" 11: 67–73. PMID 12517341] suggests that the C-terminus forms the folding nucleation site.

Ankyrin-repeat proteins have been associated with a number of human diseases; most notably, the cell cycle inhibitor p16 is associated with cancer and the Notch protein is a key component of cell signaling pathways whose intracellular repeat domain is disrupted in mutations that give rise to the neurological disorder known as CADASIL. A specialized family of ankyrin proteins known as muscle ankyrin repeat proteins (MARPs) are involved with the repair and regeneration of muscle tissue following damage due to injury and stress.Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S. (2003). The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. "J Mol Biol" 333(5):951-64. PMID 14583192 ]

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