A Particularly Discriminating Receptor.

摘要: A central challenge for systems biology is how to move beyond the characterization of processes as they occur in a given cell type under particular conditions achieve generalizable insights that can be used make accurate, quantitative predictions about system will function different circumstances (Janes and Lauffenburger, 2013xJanes, K.A. D.A. J. Cell Sci. 2013; 126: 1913–1921Crossref | PubMed Scopus (17)See all ReferencesJanes 2013). The problem arises because behavior signaling strongly dependent on detailed features cellular context, including expression levels receptor components other proteins, also influenced by crosstalk with occurring concurrently. Most critically, often regulated through dynamic modulation spatial co-localization interacting species, meaning driven local rather than cell-wide conditions. Available experimental approaches require use immortalized lines or isolated primary cells, cultured vitro highly artificial Thus, development knowledge enables extrapolation properties from one situation another critical our ability understand these vivo.An article this issue Systems (Meyer et al., 2015xMeyer, A.S., Zweemer, A.J.M., Syst. 2015; 1: 25–36Abstract Full Text PDF (4)See ReferencesMeyer 2015) illustrates combined modeling study provide quantitative, into complex process. In particular, authors focus heterogeneity distribution ligand influence response. Meyer al. examine tyrosine kinase AXL, known UFO, its ligand, growth-arrest-specific protein 6 (Gas6). AXL plays important roles immune regulation, particularly clearance apoptotic fragments debris, additionally has emerged an cancer target (Lemke, 2013xLemke, G. Cold Spring Harb. Perspect. Biol. 5: a009076Crossref (32)See ReferencesLemke, 2013).Each molecule contains both high-affinity binding site, Ig1, low-affinity Ig2, which bind distinct sites Gas6. key event activation formation signaling-competent dimer stabilized two Gas6 molecules, each bridges molecules Ig1 Ig2 (Figure 1Figure 1A) (Sasaki 2006xSasaki, T., Knyazev, P.G., Clout, N.J., Cheburkin, Y., Gohring, W., Ullrich, A., Timpl, R., Hohenester, E. EMBO 2006; 25: 80–87Crossref (95)See ReferencesSasaki 2006). It been some years lipid phosphatidylserine (PtdSer), component inner leaflet plasma membrane, role N-terminal γ-carboxylglutamic acid-rich (GLA) domain (Graham 2014xGraham, D.K., DeRyckere, D., Davies, K.D., Earp, H.S. Nat. Rev. Cancer. 2014; 14: 769–785Crossref (37)See ReferencesGraham 2014). However, published studies disagree precisely what PtdSer activation, whether it obligatory cofactor dispensable functions receptor.Figure 1Mechanism Engagement Absence Presence PtdSer(A) Molecular architecture between domains (green) C-terminal laminin G-like (blue) (PDB code 2C5D). Shown are front view (left) top (right). green arrows show direction attachment membrane.(B) absence PtdSer, dimerization 1:1 AXL-Gas6 complexes weak, such at moderate high concentrations adopts non-signaling state shown bottom.(C) When presented arrayed PtdSer-coated particle (purple), density initially formed compared KD dimerization, giving robust activated dimers.View Large Image Download PowerPoint SlideUsing careful experimentation disentangle effects exogenous those resulting autocrine signaling, were able construct model activation. Strikingly, revealed exactly interaction helps sensitize presence particulate fragments, contain exposed PtdSer-bearing membranes.This understood considering interacts PtdSer. initial complex, when binds dimerize bound unoccupied site 1B). homodimeric receptors, actually inhibit concentrations, become fully occupied separate leaving no remaining vacant satisfied (Atanasova Whitty, 2012xAtanasova, M. A. Crit. Biochem. Mol. 2012; 47: 502–530Crossref (14)See ReferencesAtanasova 2012). Even significant only if concentration exceeds equilibrium dissociation constant (KD) (Whitty Borysenko, 1999xWhitty, C.W. Chem. 1999; 6: R107–R118Abstract (28)See ReferencesWhitty 1999).In case showed that, affinity modest. Consequently, soluble induces inefficiently, inhibitory relatively low changes dramatically, however, particle, multiple molecules. organizes presents AXL-expressing dense array, limited mobility. As result, monovalent created concentration, effectively increasing driving favor dimers 1C).The proposed explains AXL’s hypersensitivity PtdSer-containing fragments. doing so, provides definitive elegant example how—to paraphrase Tip O’Neill—all local, therefore give rise very large differences system. results identify potential inhibitor discovery.The notion clustering enhance engagement is, course, means new. new combines reveal details observed response relates individual molecular events drive potentially applied predict types situations and, appropriate modifications, many receptors may mechanisms sensitization spatially distributed ligand.