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Molecular Basis of Peptide Hormone Production. Understanding Regulation of Hormone Levels How to Make a Peptide: Basic Steps Cell Structures Involved in Peptide Production Gene Structure and Transcription Processing of RNA Transcripts Translation of mRNA into Peptide

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molecular basis of peptide hormone production
Molecular Basis of Peptide Hormone Production

Understanding Regulation of Hormone Levels

How to Make a Peptide: Basic Steps

Cell Structures Involved in Peptide Production

Gene Structure and Transcription

Processing of RNA Transcripts

Translation of mRNA into Peptide

Post-translational Processing of Peptides

Secretion of Peptide Hormones

peptide protein hormones
Peptide/protein hormones
  • Range from 3 amino acids to hundreds of amino acids in size.
  • Often produced as larger molecular weight precursors that are proteolytically cleaved to the active form of the hormone.
  • Peptide/protein hormones are water soluble.
  • Comprise the largest number of hormones– perhaps in thousands
peptide protein hormones3
Peptide/protein hormones
  • Are encoded by a specific gene which is transcribed into mRNA and translated into a protein precursor called a preprohormone
  • Preprohormones are often post-translationally modified in the ER to contain carbohydrates (glycosylation)
  • Preprohormones contain signal peptides (hydrophobic amino acids) which targets them to the golgi where signal sequence is removed to form prohormone
  • Prohormone is processed into active hormone and packaged into secretory vessicles
peptide protein hormones4
Peptide/protein hormones
  • Secretory vesicles move to plasma membrane where they await a signal. Then they are exocytosed and secreted into blood stream
  • In some cases the prohormone is secreted and converted in the extracellular fluid into the active hormone: an example is angiotensin is secreted by liver and converted into active form by enzymes secreted by kidney and lung
relation of hormone production to regulation of hormone levels
Relation of Hormone Production to Regulation of Hormone Levels
  • Endocrine feedback is dependent upon the level of hormone available to act on the target tissue, and the number of receptors for that hormone in the target tissue.
  • The amount of available hormone is determined by several factors:

- rate of hormone synthesis

- rate of hormone release (from endocrine gland)

- presence of binding proteins in blood

- speed of degradation/removal (circulating half-life)

  • Today will study how peptide hormones are synthesized
what are the basic steps in making a peptide destined for secretion from the cell
What are the Basic Steps in Making a Peptide Destined for Secretion from the Cell?

gene for peptide (DNA)


primary RNA transcript



messenger RNA





mature (active) peptide


protein and polypeptide hormone receptors
Protein and Polypeptide Hormone Receptors
  • Binds to surface receptor
  • Transduction
  • System activation
    • Open ion channel
    • Enzyme activation
      • Second messenger systems
      • Protein synthesis
peptide hormones
Peptide hormones
  • Amino acids/ modified amino acids/ peptide/glycoprotein or protein
  • The receptors are on the plasma membrane
  • When hormone binds to receptor
    • Activates an enzyme to produce cyclic AMP (cAMP)
    • This activates a specific enzyme in the cell, which activates another………and so on
    • Known as an enzyme cascade
Peptide hormones:
  • Each enzyme can be used over and over again in every step of the cascade.
  • So more and more reactions take place.
  • The binding of a single hormone molecule can result in a 1000X response.
  • Fact acting, as enzymes are already present in cells.
why so many steps
Why so many steps??
  • At each step, you can get:

- regulation: you can control whether you proceed to the next step or not

- variation: you can change not only whether or not a step occurs, but the way in which it occurs. This can result in production of peptides with different activities, from a single gene.

Example: By regulating how luteinizing hormone is glycosylated (post-translational modification step), you can create LH molecules with different biological activities.

gene transcription the structure of nucleic acids and genes
Gene Transcription: The Structure of Nucleic Acids and Genes
  • The genetic information for protein structure is contained within nucleic acids
  • Two types: DNA and RNA
  • The basic building block is the nucleotide
  • phosphate group + sugar + organic base
  • In RNA the sugar is ribose, in DNA its deoxyribose
  • PO4 + ribose + organic base = RNA
  • The organic bases are adenine, guanine, cytosine, thymine (DNA only), and uracil (RNA only)
  • DNA is double-stranded, RNA is single-stranded
the structure of genes


5’-flanking region




Transcriptional region

The Structure of Genes
  • A eukaryotic gene encodes for one (or more) peptides and is typically composed of the following:




regulation of transcription by regulatory regions
Regulation of Transcription by Regulatory Regions
  • In the 5’-flanking region reside DNA sequences which regulate the transcription of gene into RNA
  • Examples:

- TATAA box: 25-30 bases upstream from initiation start site. Binds RNA polymerase II. Basic stuff required for transcription.

- CCAAT (CAT) box: binds CTF proteins

- Tissue-/cell-specific elements: limit expression to certain cell types

- response elements (enhancers): allow high degree of regulation of expression rate in a given tissue (ie, steroid response elements, cAMP-response element [CRE])

transcriptional regulation by cyclic amp
Transcriptional Regulation by Cyclic AMP
  • Some hormones bind to their receptor and increase cellular levels of cyclic AMP.
  • Cyclic AMP activates protein kinase A, which phosphorylates cyclic AMP response element-binding protein (CREB)
  • CREB binds to a response element on the 5’flanking region of target genes, turning on their transcription.
transcriptional regulation by cyclic amp18

cyclic AMP

protein kinase A





Transcriptional Regulation by Cyclic AMP


what is transcribed into rna
What is Transcribed into RNA?
  • Both exons and introns are transcribed into RNA.
  • Exons contain:

- 5’ untranslated region

- protein coding sequence

- 3’ untranslated region

    • Why bother with introns?

- allows alternative splicing of RNA into different mRNA forms (stay tuned…).

- introns may regulate process of transcription

post transcriptional processing

exon 1 2 3



Post-transcriptional Processing
  • Three major steps:

- splicing of primary RNA transcript: removal of intronic sequences

- Addition of methyl-guanine (cap) to 5’-UT

- Addition of poly-A tail to 3’-UT(at AAUAA or AUUAAA)

alternative splicing

Normal Splicing


exon 1 2 3

Alternative Splicing

exon 1 2 3

1 2 3

1 3

Alternative Splicing
  • By varying which exons are included or excluded during splicing, you get can more than one gene product from a single gene:

(occurs in nucleus)

regulation of mrna stability

3’ UT

5’ UT


coding region

binding protein

Regulation of mRNA Stability
  • In general, mRNA stability is regulated by factors binding to the 3’- untranslated region (3’-UT) of mRNAs.
  • The 3’UT often has stem-loop structures which serve as binding sites for proteins regulating stability.
  • This regulation occurs in the cytoplasm.
  • Example: Inhibin acts on pituitary to decrease FSH synthesis and release.
  • Part of inhibin’s effects reflect decreased stability (half-life) of FSHb subunit mRNA.
  • Translation from mRNA into protein occurs in ribosomes (RER, in the case of peptide hormones)
  • Codons of RNA match anticodons of tRNA, which bring in specific amino acids to ribosome complex
  • Example: AUG = methionine (first amino acid; translation start site)

Other “special” codons: UAA, UAG, UGA = termination codons (translation ends)

  • At end of translation, you get a prehormone, or preprohormone.








mRNA on ribosome






protein sorting role of post translational processing
Protein Sorting: Role of Post-translational Processing
  • How does a cell know where a translated peptide is supposed to go?

plasma membrane


other organelles


export from cell

50,000 proteins


signal sequences
Signal Sequences
  • At the amino terminus of the prepeptide, there is a signal sequence of about 15-30 amino acids, which tells the cell to send the peptide into the cisterna of the endoplasmic reticulum.
  • Inside the ER, the signal sequence is cleaved off.
  • Thus, the first 15-30 amino acids translated do not encode the functional peptide, but are a signal for export from the cell.
  • After removal of the signal sequence, you have a hormone or prohormone.
processing of prohormones

Inhibin alpha


Inhibin alpha

Processing of Prohormones
  • Some hormones are produced in an “immature” form, and require further cutting to get the active peptide hormone.
  • Prohormones are cut into final form by peptidases in the Golgi apparatus.
  • Cutting usually occurs at basic amino acids (lysine, arginine)
example pomc


aMSH clip bLPH bEndorphin



Example: POMC
  • The Proopiomelanocortin (POMC) peptide can be processed to give several different peptides, depending on regulation:

Get: melanocyte-stimulating hormone, lipoprotein hormone, beta endorphin, or ACTH, depending on how you cut it!

prehormone vs preprohormone vs prohormone
Prehormone vs. Preprohormone vs. Prohormone
  • Prehormone: signal sequence + mature peptide
  • Preprohormone: signal sequence + prohormone
  • Prohormone: precursor form of peptide (inactive, usually)
post translational modification of peptide hormones
Post-translational Modification of Peptide Hormones
  • Glycosylation: addition of carbohydrates to amino acids on the peptide, utilizing specific enzymes (transferases)
  • Function: Carbohydrate side chains play roles in subunit assembly, secretion, plasma half life, receptor binding, and signal transduction.
  • Each carbohydrate side chain is composed of several simple sugars, with a special arrangement.
  • Two types: N-linked and O-linked, which differ in the amino acids that they are attached to.
n linked and o linked glycosylation
N-linked and O-linked Glycosylation
  • N-linked sugars are bound to an asparagine residue, if the coding sequence Asn-X-Thr or Asn-X-Ser is present (X = any amino acid).
  • O-linked sugars are bound to serine/threonine residues.
  • Glycosylation begins in the RER, and is completed in the Golgi.
other post translational modifications
Other Post-translational Modifications
  • In addition, peptide hormones may be phosphorylated, acetylated, and sulfated, influencing their tertiary/quaternary structure and thus their biological activity.
subunit assembly
Subunit Assembly
  • If a peptide hormone is composed of two subunits, they must be joined in the Golgi apparatus.
  • Disulfide bridges may form between subunits or between parts of a protein to reinforce natural conformation.
secretion from cells
Secretion from Cells
  • Following production of the mature peptide hormone in the Golgi, the peptide is then packaged into secretory vesicles.
  • Secretory vesicles can stay within the cell until signaled to migrate to the plasma membrane.
  • Fusing of secretory vesicle with the plasma membrane releases hormone to outside of the cell.