Abstract
Kanadaptin is a nuclear protein of unknown function that is widely expressed in mammalian tissues. The crystal structure of the forkhead-associated (FHA) domain of human kanadaptin was determined to 1.6 Å resolution. The structure reveals an asymmetric dimer in which one monomer is complexed with a phosphopeptide mimic derived from a peptide segment from the N-terminus of a symmetry-related molecule as well as a sulfate bound to the structurally conserved phosphothreonine recognition cleft. This structure provides insights into the molecular recognition features utilized by this family of proteins and represents the first evidence that kanadaptin is likely involved in a phosphorylation-mediated signaling pathway. These results will be of use for designing experiments to further probe the function of kanadaptin.
Highlights
Kanadaptin, known as solute carrier family 4 anion exchanger member 1 adapter protein (SLC4A1AP), human lung cancer oncogene 3 protein (HLC-3) or NADAP, is widely expressed in almost all mammal tissues [1,2], localizes to the cell nucleus and mitochondria [2,3], and is part of a central proteome comprising 1,124 proteins that are ubiquitously and abundantly expressed in human cells [4]
Mouse kanadaptin was originally proposed to be an adaptor protein involved in targeting the Cl:HCO3 exchanger kAE1 to the plasma membrane and, implicated in inherited kidney disease [1] [n.b. the mouse protein in ref 1 (Uniprot O54716, 507 amino acids) represents a truncated version (,240 amino-acids shorter at the N-terminus) of the full length protein (Uniprot E9PX68, 744 amino acids)]
The structure was determined by molecular replacement in orthorhombic space group P212121 using the FHA domain of Pml1p subunit of the yeast precursor mRNA retention and splicing complex (PDB ID 3els) [9] as a phasing model, and refined to an Rcryst of 17.6% and an Rfree of 19.8%
Summary
Kanadaptin (kidney anion exchanger adaptor protein), known as solute carrier family 4 anion exchanger member 1 adapter protein (SLC4A1AP), human lung cancer oncogene 3 protein (HLC-3) or NADAP, is widely expressed in almost all mammal tissues [1,2], localizes to the cell nucleus and mitochondria [2,3], and is part of a central proteome comprising 1,124 proteins that are ubiquitously and abundantly expressed in human cells [4]. This triplet is posed to interact with the phosphoryl group on the target threonine, thereby conferring specific recognition of pThr. Sequence analysis indicates that the 796-amino-acids human kanadaptin contains at least two recognizable structured domains (Figure 1A): an FHA domain (residues 149–276) and a doublestranded RNA binding domain (residues 367–446 dsRBD). This domain architecture suggests that the nuclear protein kanadaptin might be involved in binding nucleic acids with its FHA domain serving as a regulatory module.
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