Protein Translocation to Mitochondria and Peroxisomes: Mechanisms and Pathways, Schemes and Mind Maps of Biology

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8. Post-translational Targeting of Proteins

Lecturer: Zheng Fan, Ph.D.

Department of Physiology

Lecture Outline

i. Protein movement between cellular compartments Major protein-sorting pathways Signal sequence ii. Post-translational protein translocation: An introduction iii. Translocation of proteins to the mitochondria Protein import into the mitochondrial matrix Protein import to the inner membrane of mitochondria Protein import into the intermembrane space and outer membrane of mitochondria iv. Translocation of proteins into the peroxisomes

Major Protein-Sorting Pathways

From ER

3b

3a^ 3b

Peroxisome

5

6

7

• Translation of all nuclear-encoded mRNAs is started on cytosolic ribosomes in the cytosol.
• Secretory pathway (left in the last slide): Ribosomes synthesizing nascent proteins in the secretory pathway are directed to the rough endoplasmic reticulum (ER) by an ER signal sequence (pink; steps 1 , 2). After translation is completed on the ER, these proteins can move via transport vesicles to the Golgi complex (step 3a) and peroxisome (step 3b). Further sorting delivers proteins either to the plasma membrane or exterior (step 4a) or to lysosomes (step 4b).
• Non-secretory pathways (right in the last slide): Synthesis of proteins lacking an ER signal sequence is completed on free ribosomes (step 1). Proteins without targeting sequence are released into the cytosol (the left arrow in step 2). Proteins with an organelle-specific targeting sequence (pink) are released into the cytosol first (the right arrow in step 2), but then are imported into mitochondria, peroxisomes, or the nucleus (steps 5–7).

Major Protein-Sorting Pathways

Gated transport – Cytosol ↔ Nucleus

Transmembrane transport – Cytosol → Mitochondria Cytosol → Peroxisomes Cytosol → ER

Vesicular transport – ER ↔ Golgi Golgi → Secretory vesicles → Cell exterior Cell exterior → Endosome → Lysosome ER → Peroxisomes

Protein Sorting and Vesicular Traffic

Proteins Can Move between Compartments in Three Ways

• Protein synthesis begins on ribosomes in the cytosol (except for the few in mitochondria).
• Specific amino acid sequences on some proteins, known as sorting signals, direct the newly synthesized proteins into the nucleus, the ER, mitochondria, or peroxisomes.
• Sorting signals can also direct the transport of proteins from the ER to other locations in the cell.
• Most newly synthesized proteins, however, do not have a sorting signal and consequently remain in the cytosol.

(1) Gated transport: Move between the cytosol and the nucleus.

(2) Transmembrane transport: Move across a membrane by transmembrane protein translocators.

(3) Vesicular transport: Move between compartments in membrane-enclosed vesicles.

Signal Sequences Direct Proteins to the Correct Compartments

• Each transfer pathway is guided by a specific sorting signal called signal sequence in the transported protein, which is recognized by a complementary sorting receptor.

• A short peptide sequence within the sequence of the proteins sorted to organelles and membranes (type I membrane proteins) that specifically binds to receptors on the targeted organelles.
• The core of a signal sequence contains hydrophobic residues that have a tendency to form a single alpha-helix.
• Many signal sequences begin with a short positively charged residues, which may help to enforce proper topology of the polypeptide during translocation.
• At the end of the signal sequence, typically there is a cleavage site that is recognized and cleaved by signal peptidase. The cleavage may occur either during or after completion of translocation to generate a mature protein. The free signal peptides are then digested by specific proteases.
• However this cleavage site is absent from transmembrane-domains that resemble and serve as signal sequences in membrane proteins (types II, III and multi-spanning).
• Many signal sequences can be predicted by computational analysis of protein sequences.

Signal Sequence and Structural Features

Signal Sequences Can Be Studied Using a Transfection Approach

• The synthesis of all proteins begins on ribosomes in the cytosol (except for the few in mitochondria).
• Proteins can move between subcellular compartments in three different ways.
• Signal sequences direct proteins to the correct cell compartments.

Summary of Protein Movement Between Cellular Compartments

Gated transport – Cytosol ↔ Nucleus

Transmembrane transport – Cytosol → Mitochondria Cytosol → Peroxisomes Cytosol → ER

Vesicular transport ER ↔ Golgi Golgi → Secretory vesicles → Cell exterior Cell exterior → Endosome → Lysosome ER → Peroxisomes

Protein Sorting and Vesicular Traffic

Proteins Sorting to Nucleus, Mitochandria, and Peroxisomes

Transport Vesicles; Topologically Equivalent Spaces

• In the figure, transport vesicles are membrane- bound structures that permit the lumen of an organelle to communicate with another organelle, and with the cell exterior. Transport vesicles in the secretory and endocytic pathways are called secretory vesicles and endosomes, respectively. Blue arrows indicate the vesicular traffic. (Note: Mitochondria do not take part in this communication)
• Topological equivalent. Cellular compartments are called topologically equivalent when molecules are moved between them without crossing the membrane. Spaces shown pink are topologically equivalent.

Gated transport – Cytosol ↔ Nucleus

Protein Sorting and Vesicular Traffic