PDBsum entry 1fho

Signaling protein

PDB id: 1fho

Contents

Protein chain

119 a.a.

References listed in PDB file

Key reference

Title

Structure of a ph domain from the c. Elegans muscle protein unc-89 suggests a novel function.

Authors

N.Blomberg, E.Baraldi, M.Sattler, M.Saraste, M.Nilges.

Ref.

Structure, 2000, 8, 1079-1087. [DOI no: 10.1016/S0969-2126(00)00509-8]

PubMed id

11080629

Abstract

BACKGROUND: Pleckstrin homology (PH) domains constitute a structurally conserved family present in many signaling and regulatory proteins. PH domains have been shown to bind to phospholipids, and many function in membrane targeting. They generally have a strong electrostatic polarization and interact with negatively charged phospholipids via the positive pole. On the basis of electrostatic modeling, however, we have previously identified a class of PH domains with a predominantly negative charge and predicted that these domains recognize other targets. Here, we report the first experimental structure of such a PH domain. RESULTS: The structure of the PH domain from Caenorhabditis elegans muscle protein UNC-89 has been determined by heteronuclear NMR. The domain adopts the classic PH fold, but has an unusual closed conformation of the "inositol binding loops. This creates a small opening to a deep hydrophobic pocket lined with negative charges on one side, and provides a molecular explanation for the lack of association with inositol-1,4,5-triphosphate. As predicted, the PH domain of UNC-89 has a strongly negative overall electrostatic potential. Modeling the Dbl homology (DH)-linked PH domains from the C. elegans genome shows that a large proportion of these modules are negatively charged. CONCLUSIONS: We present the first structure of a PH domain with a strong negative overall electrostatic potential. The presence of a deep pocket lined with negative charges suggests that the domain binds to ligands other than acidic phospholipids. The abundance of this class of PH domain in the C. elegans genome suggests a prominent role in mediating protein-protein interactions.

Figure 5.
Figure 5. Charged Surface around Hydrophobic PocketCharged surface of the UNC-89 PH domain in the same orientation as in Figure 4 and (b) turned 90° so as to view the pocket between the b1-b2 and b3-b4 loop. Blue regions correspond to a positive surface potential, red to a negative. The arrow points into the opening of the hydrophobic pocket

The above figure is reprinted by permission from Cell Press: Structure (2000, 8, 1079-1087) copyright 2000.

Secondary reference #1

Title

1h, 15n, And 13c resonance assignment of the ph domain from c. Elegans unc-89.

Authors

N.Blomberg, M.Sattler, M.Nilges.

Ref.

J Biomol Nmr, 1999, 15, 269-270.

PubMed id

10677831

Secondary reference #2

Title

Classification of protein sequences by homology modeling and quantitative analysis of electrostatic similarity.

Authors

N.Blomberg, R.R.Gabdoulline, M.Nilges, R.C.Wade.

Ref.

Proteins, 1999, 37, 379-387. [DOI no: 10.1002/(SICI)1097-0134(19991115)37:3<379::AID-PROT6>3.0.CO;2-K]

PubMed id

10591098

Figure 3.
Figure 3. Comparison of similarity indices for different descriptions of the electrostatic potentials (modeled structures only). A: Poisson-Boltzmann (PB) potential at 0 mM ionic strength versus PB potential at 150 mM. B: Analytical potential versus PB potential at 0 mM ionic strength. C: Analytical potential versus PB potential at 150 mM ionic strength.

Figure 6.
Figure 6. Display of the electrostatic potential calculated at 0 mM ionic strength for DH-linked PH domains and internal repeat PH domains on the first two principal components of the similarity matrix (cf. Fig. 5B). The key to the numbering is in Table I.

The above figures are reproduced from the cited reference with permission from John Wiley & Sons, Inc.

Secondary reference #3

Title

Functional diversity of ph domains: an exhaustive modelling study.

Authors

N.Blomberg, M.Nilges.

Ref.

Fold Des, 1997, 2, 343-355. [DOI no: 10.1016/S1359-0278(97)00048-5]

PubMed id

9427008