Receptor-type tyrosine phosphatase ligands: looking for the needle in the haystack.

Reversible protein phosphorylation plays a pivotal role in intercellular communication. Together with protein tyrosine kinases, protein tyrosine phosphatases (PTPs) are involved in the regulation of key cellular processes by controlling the phosphorylation levels of diverse effectors. Among PTPs, receptor-like protein tyrosine phosphatases (RPTPs) are involved in important developmental processes, particularly in the formation of the nervous system. Until recently, few ligands had been identified for RPTPs, making it difficult to grasp the effects these receptors have on cellular processes, as well as the mechanisms through which their functions are mediated. However, several potential RPTP ligands have now been identified to provide us with unparalleled insights into RPTP function. In this review, we focus on the nature and biological outcomes of these extracellular interactions between RPTPs and their associated ligands.

Comment on "transient-state fluctuationlike relation for the driving force on a biomolecule".

Two analytically tractable systems, Brownian particles in (i) moving harmonic oscillator or (ii) with a time-dependent natural frequency, obey a force fluctuation theorem similar to that proposed by Ponmurugan and Vemparala [Phys. Rev. E 84, 060101(R) (2011)]. Many of their results can be explained by using the former case as a model.

A complex between contactin-1 and the protein tyrosine phosphatase PTPRZ controls the development of oligodendrocyte precursor cells.

The six members of the contactin (CNTN) family of neural cell adhesion molecules are involved in the formation and maintenance of the central nervous system (CNS) and have been linked to mental retardation and neuropsychiatric disorders such as autism. Five of the six CNTNs bind to the homologous receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ), but the biological roles of these interactions remain unclear. We report here the cocrystal structure of the carbonic anhydrase-like domain of PTPRZ bound to tandem Ig repeats of CNTN1 and combine these structural data with binding assays to show that PTPRZ binds specifically to CNTN1 expressed at the surface of oligodendrocyte precursor cells. Furthermore, analyses of glial cell populations in wild-type and PTPRZ-deficient mice show that the binding of PTPRZ to CNTN1 expressed at the surface of oligodendrocyte precursor cells inhibits their proliferation and promotes their development into mature oligodendrocytes. Overall, these results implicate the PTPRZ/CNTN1 complex as a previously unknown modulator of oligodendrogenesis.

Two-photon nano-PEBBLE sensors: subcellular pH measurements.

Intracellular pH mapping is of great importance as it plays a critical role in many cellular events. Also, in tissue, pH mapping can be an indicator for the onset of cancer. Here we describe a biocompatible, targeted, ratiometric, fluorescent, pH sensing nano-PEBBLE (Photonic Explorer for Biomedical use with Biologically Localized Embedding) that is based on two-photon excitation. Two-photon excitation minimizes the photobleaching and cell autofluorescence drastically, leading to an increase in the signal-to-noise ratio. PEBBLE nanosensors provide a novel approach for introducing membrane impermeant dyes, like HPTS, into cells. We use both non-targeted and F3 peptide targeted PEBBLE nanosensors for intracellular pH measurement of 9L cells. The intracellular measurements suggest that the non-targeted nanosensors are mostly trapped in endosomes, whereas the F3 peptide targeting enables them to escape/avoid these acidic compartments. Combining the advantages of pH sensitive PEBBLE nanoparticles, including their specific targeting, with the advantages of two-photon microscopy provides an attractive and promising prospect for non-invasive real-time monitoring of pH inside cancer cells and tissues.

Transient-state fluctuationlike relation for the driving force on a biomolecule.

In experiments and simulations the force acting on a single biomolecular system has been observed as a fluctuating quantity if the system is driven under constant velocity. We ask the question that is analogous to transient state entropy production and work fluctuation relations whether the force fluctuations observed in the single biomolecular system satisfy a transient state fluctuationlike relation, and the answer is in the affirmative. Using a constant velocity pulling steered molecular dynamics simulation study for protein unfolding, we confirm that the force fluctuations of this single biomolecular system satisfy a transient-state fluctuationlike relation 1/γ(T,v) ln[P(v)(+f)/P(v)(-f)] = f. P(v)(±f) is the probability of positive and negative values of forces f = f · for a given unfolding velocity of magnitude v and the pulling direction n, nis the unit vector of n, and γ(T,v) is a factor that depends on initial equilibrium temperature T and the unfolding velocity. For different unfolding velocities we find that the system in the nonequilibrium pulling region displays substantial negative fluctuation in its unfolding force when velocity decreases. A negative value of force may indicate the emergence of refolding behavior during protein unfolding. We also find that γ(T,v) ~ T(-δ)v(α) and the system relaxation time τ(T,v) ~ T(δ)v(-(1+α), where α and δ are scaling exponents.