TLP

TLP (PF3D7_0616500) is a TRAP/MIC2-family type I transmembrane adhesin expressed predominantly in salivary-gland sporozoites of P. falciparum and P. berghei that is specifically required for productive cell traversal and efficient intradermal migration (PMID:18346224, PMID:22306356). As a functional TRAP-family member, its cytoplasmic tail binds aldolase, physically coupling extracellular adhesion to the parasite actin-myosin motor, yet genetic disruption in P. berghei shows the protein is non-vital and redundant during life-cycle progression, leaving in vitro gliding motility and hepatocyte invasion per se intact (PMID:18346224, PMID:18441124). Beyond invasin function, TLP organizes sporozoite adhesion, acting together with TRAP, S6, and actin filaments to establish efficient attachment before motility, such that tlp(-) sporozoites adhere and disperse abnormally and are delayed in infecting the host (PMID:20159960, PMID:21698220). Biophysically, TLP modulates actin dynamics to couple retrograde actin flow to traction-force generation: tlp(-) sporozoites exhibit elevated retrograde flow but reduced force output and lower, disorganized ventral traction forces, marking TLP as an element of the sporozoite force-generating machinery (PMID:26792112, PMID:40716091). All mechanistic characterization derives from P. berghei knockout studies; no direct biochemical or structural analysis of the P. falciparum protein appears in the available corpus.

1. 2008 High

   Establishing whether TLP had a distinct role among TRAP-family adhesins, targeted disruption defined it as specifically required for sporozoite cell traversal rather than motility or invasion.

   Evidence targeted gene knockout in P. berghei with cell traversal, in vitro motility, and in vivo infectivity assays

   PMID:18346224

   Open questions at the time

   • Molecular basis of the traversal-specific requirement not defined
   • No characterization of the P. falciparum protein directly
   • Extracellular ligand/receptor not identified
2. 2008 High

   To connect TLP's surface adhesion to the motor, aldolase binding by its cytoplasmic tail was shown, placing TLP in the TRAP-family adhesion-to-actomyosin linkage while genetics confirmed a redundant, non-vital role.

   Evidence in vitro aldolase-binding assay with genetic disruption and complementation in P. berghei

   PMID:18441124

   Open questions at the time

   • Direct structural definition of the tail-aldolase interface absent
   • Extent of functional redundancy with other TRAP-family members unquantified
3. 2010 Medium

   Asking how TLP contributes before motility begins, imaging showed it organizes efficient sporozoite adhesion under static conditions in concert with TRAP, S6, and actin filaments.

   Evidence TIRF microscopy and flow adhesion assays on tlp(-) versus wild-type P. berghei sporozoites

   PMID:20159960

   Open questions at the time

   • Direct physical interaction between TLP, TRAP, and S6 not demonstrated
   • Mechanism of adhesion organization unresolved
4. 2011 Medium

   To explain infection delay in vivo, quantitative migration analysis linked TLP-dependent adhesion to normal coupling of speed, persistence, and dispersal in structured environments.

   Evidence intravital imaging and micro-fabricated obstacle arrays with tlp(-) P. berghei sporozoites

   PMID:21698220

   Open questions at the time

   • Molecular determinants of adhesion strength not mapped
   • Contribution of specific tissue substrates unresolved
5. 2012 Medium

   Distinguishing wounding from passage, knockout sporozoites were shown to be retained inside host cytoplasm, establishing TLP as required for productive traversal (passage-through) rather than mere cell wounding.

   Evidence MDCK monolayer traversal assay with fluorescence microscopy of tlp knockout P. berghei sporozoites

   PMID:22306356

   Open questions at the time

   • Egress step defect not mechanistically defined
   • Molecular partners at the exit membrane unknown
6. 2016 Medium

   Probing how TLP shapes force production, optical tweezers revealed that tlp(-) sporozoites have higher retrograde flow but lower force, implicating TLP in coupling actin retrograde flow to adhesive force buildup.

   Evidence optical tweezers measurement of retrograde flow and force in tlp(-) versus wild-type P. berghei sporozoites

   PMID:26792112

   Open questions at the time

   • Direct effect of TLP on actin filament dynamics not visualized
   • Whether TLP acts through aldolase-actin linkage in this context untested
7. 2016 Low

   Addressing how TLP reaches the surface, a PAT knockout that blocks secretion of TRAP-family microneme adhesins implicated TLP secretion downstream of PAT-regulated vesicle fusion.

   Evidence PAT genetic disruption with secretion and motility assays in P. berghei

   PMID:27427910

   Open questions at the time

   • TLP secretion inferred as part of a broad TRAP-family class, not individually confirmed
   • Direct demonstration of TLP micronemal residence and PAT-dependent surface delivery absent
8. 2025 Medium

   Directly measuring traction, force microscopy showed tlp(-) sporozoites generate lower and disorganized ventral traction forces, confirming TLP as an element of the sporozoite force-generating machinery.

   Evidence traction force microscopy on wild-type and tlp(-) P. berghei sporozoites

   PMID:40716091

   Open questions at the time

   • Molecular link between TLP and traction foci organization unresolved
   • Relationship to the aldolase-actin motor connection not established

• How TLP molecularly organizes adhesion and actin dynamics to enable traversal, and whether the P. falciparum protein behaves as its P. berghei ortholog, remain open.
• No extracellular ligand/receptor identified
• No structural model of the adhesin or its aldolase-binding tail
• P. falciparum TLP not functionally characterized directly