PDBsum entry 1d9s

Signaling protein

PDB id

1d9s

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Contents

			Protein chain

					136 a.a. *

* Residue conservation analysis

PDB id:

1d9s

Links

Name:

Signaling protein

Title:

Tumor suppressor p15(ink4b) structure by comparative modeling and nmr data

Structure:

Cyclin-dependent kinase 4 inhibitor b. Chain: a. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

10 models

Authors:

C.Yuan,L.Ji,T.L.Selby,I.J.L.Byeon,M.D.Tsai

Key ref:

C.Yuan et al. (1999). Tumor suppressor INK4: comparisons of conformational properties between p16(INK4A) and p18(INK4C). J Mol Biol, 294, 201-211. PubMed id: 10556039 DOI: 10.1006/jmbi.1999.3231

Date:

29-Oct-99

Release date:

28-Jul-00

PROCHECK

	Headers

	References

Protein chain

P55271 (CDN2B_MOUSE) - Cyclin-dependent kinase 4 inhibitor B from Mus musculus

Seq: Struc:					130 a.a. 136 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.?

[IntEnz] [ExPASy] [KEGG] [BRENDA]

DOI no: 10.1006/jmbi.1999.3231	J Mol Biol 294:201-211 (1999)
PubMed id: 10556039

Tumor suppressor INK4: comparisons of conformational properties between p16(INK4A) and p18(INK4C).
C.Yuan, J.Li, T.L.Selby, I.J.Byeon, M.D.Tsai.

ABSTRACT

The INK4 (inhibitor of cyclin-dependent kinase 4) family consists of four tumor-suppressor proteins: p15(INK4B), p16(INK4A), p18(INK4C), and p19(INK4D). While their sequences and structures are highly homologous, they show appreciable differences in conformational flexibility, stability, and aggregation tendency. Here, p16 and p18 were first compared directly by NMR for line broadening and disappearance, then investigated by three different approaches in search of the causes of these differences. From denaturation experiments it was found that both proteins are marginally stable with low denaturation stability (1.94 and 2.98 kcal/mol, respectively). Heteronuclear (1)H-(15)N nuclear Overhauser enhancement measurements revealed very limited conformational flexibility on the pico- to nanosecond time-scale for both p16 and p18. H/(2)H exchange of amide protons monitored by NMR on three proteins (p16, p18 as well as p15), however, revealed markedly different rates in the order p18<p16</=p15. A subset of very slowly exchanging residues (about 19 in total) was identified in p18, including 16 residues in the region of the fourth ankyrin repeat, probably as a result of a stabilizing effect by the extra ankyrin repeat. Thus, while INK4 proteins may have similar low thermodynamic stability as well as limited flexibility on the pico- to nanosecond time-scale, they display pronounced differences in the conformational flexibility on the time-scale of minutes to hours. Further analyses suggested that differences in H/(2)H exchange rates reflect differences in the kinetic stability of the INK4 proteins, which in turn is related to differences in the aggregation tendency.

Selected figure(s)



	Figure 1. Figure 1. Overlay of ribbon diagrams of p15, p16, and p18 solution structures with the ankyrin repeats num- bered. The Figure was generated with the Insight II software (Molecular Simulations Inc.).		Figure 7. Figure 7. Overall H/ 2 H exchange rate constants extracted by fitting the time-course data of total peak volumes to equation (1) for p15 and p16 and to equation (1) as well as equation (2) for p18.

Figures were selected by an automated process.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21053367

N.Fahham, S.Sardari, S.N.Ostad, B.Vaziri, and M.H.Ghahremani (2010).
C-terminal domain of p16(INK4a) is adequate in inducing cell cycle arrest, growth inhibition and CDK4/6 interaction similar to the full length protein in HT-1080 fibrosarcoma cells.

J Cell Biochem, 111, 1598-1606.

20333375

S.C.Yadav, M.V.Jagannadham, and S.Kundu (2010).
Equilibrium unfolding of kinetically stable serine protease milin: the presence of various active and inactive dimeric intermediates.

Eur Biophys J, 39, 1385-1396.

19591507

C.F.Cervantes, P.R.Markwick, S.C.Sue, J.A.McCammon, H.J.Dyson, and E.A.Komives (2009).
Functional dynamics of the folded ankyrin repeats of I kappa B alpha revealed by nuclear magnetic resonance.

Biochemistry, 48, 8023-8031.

19154236

H.McKenzie, T.M.Becker, L.L.Scurr, R.F.Kefford, and H.Rizos (2009).
Wild type and melanoma-associated mutant p16 proteins do not oligomerize in vivo.

Pigment Cell Melanoma Res, 22, 131-133.

19352455

N.Fahham, M.H.Ghahremani, S.Sardari, B.Vaziri, and S.N.Ostad (2009).
Simulation of Different Truncated p16 Forms and In Silico Study of Interaction with Cdk4.

Cancer Inform, 7, 1.

18305166

C.Löw, U.Weininger, P.Neumann, M.Klepsch, H.Lilie, M.T.Stubbs, and J.Balbach (2008).
Structural insights into an equilibrium folding intermediate of an archaeal ankyrin repeat protein.

Proc Natl Acad Sci U S A, 105, 3779-3784.

PDB code:

2rfm

17483458

N.D.Werbeck, and L.S.Itzhaki (2007).
Probing a moving target with a plastic unfolding intermediate of an ankyrin-repeat protein.

Proc Natl Acad Sci U S A, 104, 7863-7868.

16596641

G.Interlandi, G.Settanni, and A.Caflisch (2006).
Unfolding transition state and intermediates of the tumor suppressor p16INK4a investigated by molecular dynamics simulations.

Proteins, 64, 178-192.

16584130

J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.

AAPS J, 8, E204-E221.

15215520

C.H.Croy, S.Bergqvist, T.Huxford, G.Ghosh, and E.A.Komives (2004).
Biophysical characterization of the free IkappaBalpha ankyrin repeat domain in solution.

Protein Sci, 13, 1767-1777.

12009890

B.Zhang, and Z.Y.Peng (2002).
Structural consequences of tumor-derived mutations in p16INK4a probed by limited proteolysis.

Biochemistry, 41, 6293-6302.

10892805

C.Yuan, T.L.Selby, J.Li, I.J.Byeon, and M.D.Tsai (2000).
Tumor suppressor INK4: refinement of p16INK4A structure and determination of p15INK4B structure by comparative modeling and NMR data.

Protein Sci, 9, 1120-1128.

PDB code:

1dc2

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.