Database Accession: DI1000039
Name: Nuclear NIPP1:PP1 Holoenzyme
PDB ID: 3v4y
Experimental method: X-ray (2.10 Å)
Source organism: Homo sapiens
Proof of disorder:
Kd: 1.04×10-07 M
Primary publication of the structure:
O'Connell N, Nichols SR, Heroes E, Beullens M, Bollen M, Peti W, Page R
The Molecular Basis for Substrate Specificity of the Nuclear NIPP1:PP1 Holoenzyme.
(2012) Structure 20: 1746-56
PMID: 22940584
Abstract:
Regulation of protein phosphatase 1 (PP1) is controlled by a diverse array of regulatory proteins. However, how these proteins direct PP1 specificity is not well understood. More than one-third of the nuclear pool of PP1 forms a holoenzyme with the nuclear inhibitor of PP1, NIPP1, to regulate chromatin remodeling, among other essential biological functions. Here, we show that the PP1-binding domain of NIPP1 is an intrinsically disordered protein, which binds PP1 in an unexpected manner. NIPP1 forms an α helix that engages PP1 at a unique interaction site, using polar rather than hydrophobic contacts. Importantly, the structure also reveals a shared PP1 interaction site outside of the RVxF motif, the ΦΦ motif. Finally, we show that NIPP1:PP1 substrate selectivity is determined by altered electrostatics and enhanced substrate localization. Together, our results provide the molecular basis by which NIPP1 directs PP1 substrate specificity in the nucleus.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
hydrolase activity, acting on ester bonds Catalysis of the hydrolysis of any ester bond.
Biological process:
primary metabolic process The chemical reactions and pathways involving those compounds which are formed as a part of the normal anabolic and catabolic processes. These processes take place in most, if not all, cells of the organism.
macromolecule metabolic process The chemical reactions and pathways involving macromolecules, any molecule of high relative molecular mass, the structure of which essentially comprises the multiple repetition of units derived, actually or conceptually, from molecules of low relative molecular mass.
regulation of cellular macromolecule biosynthetic process Any process that modulates the frequency, rate or extent of cellular macromolecule biosynthetic process.
negative regulation of molecular function Any process that stops or reduces the rate or extent of a molecular function, an elemental biological activity occurring at the molecular level, such as catalysis or binding.
regulation of cellular protein metabolic process Any process that modulates the frequency, rate or extent of the chemical reactions and pathways involving a protein, occurring at the level of an individual cell.
Cellular component:
nucleoplasm That part of the nuclear content other than the chromosomes or the nucleolus.
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: B, A
Notes: Chains C, D, E, F, G and H were removed as chains A and B represent the biologically relevant interaction.
Name: Nuclear inhibitor of protein phosphatase 1
Source organism: Homo sapiens
Length: 55 residues
Sequence:Sequence according to PDB SEQRESETELDNLTEFNTAHNKRISTLTIEEGNLDIQRPKRKRKNSRVTFSEDDEIINPED
UniProtKB AC: Q12972 (positions: 160-214) Coverage: 15.7%
UniRef90 AC: UniRef90_Q12972 (positions: 160-214)
Name: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit
Source organism: Homo sapiens
Length: 293 residues
Sequence:Sequence according to PDB SEQRESLNLDSIIGRLLEVQGSRPGKNVQLTENEIRGLCLKSREIFLSQPILLELEAPLKICGDIHGQYYDLLRLFEYGGFPPESNYLFLGDYVDRGKQSLETICLLLAYKIKYPENFFLLRGNHECASINRIYGFYDECKRRYNIKLWKTFTDCFNCLPIAAIVDEKIFCCHGGLSPDLQSMEQIRRIMRPTDVPDQGLLCDLLWSDPDKDVQGWGENDRGVSFTFGAEVVAKFLHKHDLDLICRAHQVVEDGYEFFAKRQLVTLFSAPNYCGEFDNAGAMMSVDETLMCSFQILKPA
UniProtKB AC: P62136 (positions: 7-299) Coverage: 88.8%
UniRef90 AC: UniRef90_P62136 (positions: 7-299)
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Chain B:
The interacting region of NIPP1 has been shown to be intrinsically disordered (PMID: 22940584). The 144-225 region described in DisProt entry DP00937 covers 100% of the sequence present in the structure. The protein region involved in the interaction contains a known functional nuclear localization signal (See more). The protein region involved in the interaction contains a RVXF PP1-binding motif (PMID: 22940584).
Chain A:
The calcineurin-like phosphoesterase domain involved in the interaction is known to adopt a stable structure in isolation (see Pfam domain PF00149). A solved monomeric structure of the domain is represented by PDB ID 4mov.
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). No related structure was found in the Protein Data Bank.
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