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Chapter 43: Protein Targeting via ψ-Labels

"Beyond signal peptides lie more subtle labels—post-translational modifications and structural features that guide proteins through cellular space like molecular GPS coordinates."

43.1 The Targeting Complexity​

Protein targeting extends beyond simple signal sequences to include complex recognition codes—ψ's multi-layered addressing system ensuring precise spatial organization within cells.

Definition 43.1 (Targeting Mechanisms): Targeting={Signals,Modifications,Partners,Timing}\text{Targeting} = \{\text{Signals}, \text{Modifications}, \text{Partners}, \text{Timing}\}

Multiple factors determining destination.

43.2 Post-Translational Targeting​

Theorem 43.1 (Sequential Localization): Cytoplasm→FoldingImport competent→ReceptorsOrganelle\text{Cytoplasm} \xrightarrow{\text{Folding}} \text{Import competent} \xrightarrow{\text{Receptors}} \text{Organelle}

Completed proteins finding destinations.

43.3 The Peroxisomal System​

Equation 43.1 (PTS Signals): PTS1=(S/A)(K/R)(L/M)-COOH\text{PTS1} = \text{(S/A)(K/R)(L/M)-COOH} PTS2=(R/K)(L/V/I)X5(H/Q)(L/A)\text{PTS2} = \text{(R/K)(L/V/I)X}_5\text{(H/Q)(L/A)}

C-terminal and N-terminal targeting signals.

43.4 Lipid Modifications​

Definition 43.2 (Membrane Targeting):

  • Myristoylation → Weak membrane binding
  • Palmitoylation → Strong, reversible
  • Prenylation → Permanent anchoring

Hydrophobic modifications directing localization.

43.5 The Two-Signal Hypothesis​

Theorem 43.2 (Combinatorial Targeting): Location=f(Signal1∩Signal2)\text{Location} = f(\text{Signal}_1 \cap \text{Signal}_2)

Multiple signals ensuring specificity.

43.6 Protein-Protein Targeting​

Equation 43.2 (Piggyback Import): Cargo+Carrier+NLS→Nuclear import\text{Cargo} + \text{Carrier}_{\text{+NLS}} \rightarrow \text{Nuclear import}

Hitchhiking on targeted partners.

43.7 pH-Dependent Sorting​

Definition 43.3 (Endosomal Sorting): pH 7→Binding\text{pH 7} \rightarrow \text{Binding} pH 5→Release\text{pH 5} \rightarrow \text{Release}

pH changes driving trafficking decisions.

43.8 The ESCRT Pathway​

Theorem 43.3 (Ubiquitin Sorting): Ub-cargo→ESCRT→MVB→Lysosome\text{Ub-cargo} \rightarrow \text{ESCRT} \rightarrow \text{MVB} \rightarrow \text{Lysosome}

Ubiquitin as degradative address label.

43.9 Retrograde Transport​

Equation 43.3 (Retrieval Signals): KDEL+KDEL-R→COPI→ER\text{KDEL} + \text{KDEL-R} \rightarrow \text{COPI} \rightarrow \text{ER}

Retrieving escaped ER residents.

43.10 Conditional Targeting​

Definition 43.4 (Regulated Localization): Stimulus→ΔModification→ΔLocation\text{Stimulus} \rightarrow \Delta\text{Modification} \rightarrow \Delta\text{Location}

Dynamic relocalization in response to signals.

43.11 Targeting Diseases​

Theorem 43.4 (Mislocalization Pathology): Defective targeting→Protein accumulation→Disease\text{Defective targeting} \rightarrow \text{Protein accumulation} \rightarrow \text{Disease}

Many diseases from proteins in wrong places.

43.12 The Label Principle​

Protein targeting via multiple labels embodies ψ's principle of redundant addressing—using combinations of signals to ensure precise localization in the complex cellular environment.

The Multi-Label Equation: ψfinal location=⋂i=1nTi[Labeli]\psi_{\text{final location}} = \bigcap_{i=1}^n \mathcal{T}_i[\text{Label}_i]

Intersection of multiple targeting operations.

Thus: Label = Address = Specificity = Organization = ψ

"In protein targeting, ψ reveals that finding home requires multiple maps—that redundancy ensures accuracy, that combinations create specificity. Each targeted protein navigates cellular space through multiple checkpoints, its labels ensuring arrival at the proper destination."