LL5ß

 

LL5ß was initially identified from the database and is a protein that contains a pleckstrin homology (PH) binding domain [1][4]. It can selectively bind to phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) via its PH domain [1].

 

LL5ß has the potentiality to respond to the activation of type I PI3Ks and move to plasma membrane. Its intracellular distribution depends on the cellular concentration of PI(3,4,5)P3. When PI(3,4,5)P3 is relatively low, the binding affinity of LL5ß is lost and thus driven to vesicular compartments [1].

 

LL5ß is found to interact with cytoskeleton protein actin-associated filamin [1][4].  When PI(3,4,5)P3 aggregates at the leading edge of lamellipodium (the actin projection on the leading edge of a cell), filamin A answers calls from LL5ß and migrate to the site of PI(3,4,5)P3, subsequently recruiting SHIP2. Thus PI(3,4,5)P3 is under the control by SHIP2 through a reciprocal feedback loop [4][5]. LL5ß is a regulator of SHIP2 translocation. Collectively LL5ß ensures cell dynamics occur in a single direction [5]. In addition, LL5ß is in charge of stabilizing microtubule through its communication with cytoplasmic linker-associated proteins (CLASPs) that bind to the (+) ends of microtubules [5].

 

LL5ß immediately move to cell membrane in response to epidermal growth factor treatment [5]. Under certain unfavourable conditions for survival, such as depletion of growth factors, it is notable that LL5ß undergoes a drastic redistribution although the underlying mechanism of interaction between LL5ß and PI3K remains obscure [1].

 

At neuromuscular junction LL5ß mediates and restricts the accumulation of acetylcholine receptor (AChR) at the postsynaptic membrane [1].  

 

 

Phosphoinsotide 3-kinase (PI3K)

 

Phosphoinositides are phosphorylated by PI3K by attaching phosphate groups at 3’ position. Among the three types of PI3Ks, a large number of membrane surface receptor could induce the activation of type I PI3K and leads to the aggregation of PI (3,4,5)P3 at the inner cell membrane. PI (3,4,5)P3 is a powerful signal transducer and recruit cytosolic proteins with PI (3,4,5)P3-binding structure. These PI3K effectors such as PKD-1 and PKB shift to the inner leaflet of plasma membrane when the receptor of PI3K is stimulated and bind to phospholipids through their PH domain [1].

 

 

PH domain

 

This protein module is approximately 120 amino acids long and can be found in a large group of proteins [2]. Among the most common protein domains in human genome, PH domain is found to be the 11th most abundant modular protein [2] [3]. It was first described in 1993 and named such a fact that its amino acid sequence was highly invariant to the one of such regions in pleckstrin which is phosphorylated by protein kinase C in platelet [3].

 

Its spectrum of versatility that mainly involves intracellular signaling cascade, membrane trafficking, cytoskeleton composition and phospholipid modification is conferred by a variety of binding ligands, ranging from membrane phospholipids to proteins [2][3]. Commonly, the binding of PH domain to PI (3,4,5)P3 and phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) via either direct interaction or indirect contact through derivatives of head groups, is of high specificity and strong affinity [2]. It also recognizes the βγ-subunits of G-protein and protein kinase C [3]. Therefore, PH domain functions as an anchor of membrane phospholipids [2].

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1. The structure of PH Domain [2]

a strongly bent seven stranded antiparallel β-sheet, closed on one end by a characteristic C-terminal α-helix

 

References:

1. Paranavitane, V., Coadwell, W. J., Eguinoa, A., Hawkins, P.T., Stephens, L. (2002) LL5beta is a phosphatidylinositol (3,4,5)-trisphosphate sensor that can bind the cytoskeletal adaptor, gamma-filamin. Journal of Biological Chemistry 278(2):1328-35  

2. Scheffzek, K., Welti, S. (2012) Pleckstrin homology (PH) like domains – versatile modules in protein–protein interaction platforms. FEBS Letters 586(17):2662-2673 

3. Lemmon, M. A. (2007) Pleckstrin homology (PH) domains and phosphoinositides. Biochemistry Society Symposium (74):81-93

4. Kishi, M., Kummer, T., Eglen, S. J., Sanes, J. R. (2005) LL5: a regulator of postsynaptic differentiation identified in a screen for synaptically enriched transcripts at the neuromuscular junction. Journal of Cell Biology 169(2):355-366 

5. Takabayashi, T., Xie, M. J., Takeuchi, S. et al. (2010) LL5beta directs the translocation of filamin A and SHIP2 to sites of phosphatidylinositol 3,4,5-triphosphate accumulation, and PtdIns(3,4,5)P3 localization is mutually modified by co-recruited SHIP2. Journal of biological chemistry 285(21):16155-16165