Pleckstrin homology (PH) domains and phosphoinositides

Abstract

Pleckstrin homology (PH) domains represent the 11 th most common domain in the human proteome. They are best known for their ability to bind phosphoinositides with high affinity and specificity, although it is now clear that less than 10% of all PH domains share this property. Cases in which PH domains bind specific phosphoinositides with high affinity are restricted to those phosphoinositides that have a pair of adjacent phosphates in their inositol headgroup. Those that do not (PtdIns3P, PtdIns5P and PtdIns(3,5)P 2 ) are instead recognized by distinct classes of domains including FYVE domains, phox homology (PX) domains, PHD fingers, and the recently identified PROPPINs. Of the 90% of PH domains that do not bind strongly and specifically to phosphoinositides, few are well understood. One group of PH domains appears to bind both phosphoinositides (with little specificity) and Arf family small G-proteins, and are targeted to the Golgi apparatus where both phosphoinositides and the relevant Arfs are both present. Here, the PH domains may function as coincidence detectors. A central challenge in understanding the majority of PH domains to establish whether the very low affinity phosphoinositide binding reported in many cases has any functional relevance. For PH domains from dynamin and from Dbl family proteins, this weak binding does appear to be functionally important, although its precise mechanistic role is unclear. In many other cases, it is quite likely that alternative binding partners are more relevant, and that the observed PH domain homology represents conservation of structural fold rather than function.

Discovery of novel membrane binding structures and functions

“…The PH domain is one of the most common structural domains in mammalian proteomes (Lemmon 2007), being present in more than 320 human proteins. The domain is known to mediate a variety of functions, including targeting cellular membranes by specific binding to PIs, and many others binding to proteins (Lemmon 2007).…”

“…The PH domain is one of the most common structural domains in mammalian proteomes (Lemmon 2007), being present in more than 320 human proteins. The domain is known to mediate a variety of functions, including targeting cellular membranes by specific binding to PIs, and many others binding to proteins (Lemmon 2007). These two functional types of PH proteins can be represented by the phosphoinositol 4-phosphate adaptor protein 1 (FAPP1) and the serine/threonine-protein kinase D1 (PKD1) proteins, respectively.…”

“…Although several structural motifs that bind membranes have been identified, their functions are often poorly conserved. For example only about 10% of PH domains have been estimated to bind membranes, with many others binding instead to proteins (Lemmon 2007). Moreover, even those families whose abilities to bind membranes are well-conserved, like PX domains, exhibit diverse lipid specificities and membrane affinities (Lemmon 2003).…”

An Autoinhibitory Role for the Pleckstrin Homology Domain of Interleukin-2-Inducible Tyrosine Kinase and Its Interplay with Canonical Phospholipid Recognition

“…The residues located on β-strands 2-4 are circled and those on the α-helix are boxed. All structural figures were made using PyMol 8 .…”

Calmodulin and PI(3,4,5)P 3 cooperatively bind to the Itk pleckstrin homology domain to promote efficient calcium signaling and IL-17A production

“…PH domains are generally recognized as membrane-targeting domains (4, 5); although these domains may have other functions as well. Lipid-binding PH domains have positively charged residues in the loops between specific β strands (β1/β2, β3/β4, and β6/β7) and these charged residues differentially interact with negatively charged lipids, including phosphoinositides, such as phosphatidylinositol-4-phosphate [PI4P], phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ], phosphatidylinositol-3,4-bisphosphate [PI(3,4)P 2 ], and phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P 3 ] (1). Although most lipid-binding PH domains interact weakly or promiscuously with a range of lipid targets, a few PH domains have high specificity and submicromolar affinity for specific phospholipids (1).…”